• 18 years of age or older undergoing an IUI procedure.
• IUI must be performed in the offices at Mayo Clinic in Rochester, MN or Eau Claire, WI.
• IUI procedure must be on a weekday.
• IUI procedure is scheduled to be completed by a nurse.

• Non-English speaking.
• IUI procedure on a weekend day.
• IUI procedure is scheduled with an MD provider (known or expected to be difficult).
• Planned IUI procedure is cancelled prior to undergoing the procedure.
• The patient has a documented diagnosis of complete hearing loss or significant hearing impairment in both ears.
• The patient has previous participated or declined enrollment in the study during a prior IUI procedure.

Eligibility last updated 6/14/23. Questions regarding updates should be directed to the study team contact.

• Informed consent obtained before any trial-related activity.
• Age ≥ 18 years and ≤ 90 years at Screening.
• Diagnosis of SBS and with the latest intestinal resection being at least 6 months prior to Screening and considered stable with regard to PS need. No restorative surgery planned in the trial period.
• Requiring PS at least 3 days per week.
• Willing to adhere to an individual pre-defined drinking menu during 48-hours measuring intervals.
• Willing to maintain a stable weight (± 5%) for the duration of the trial (24 weeks).
• Having:
  • A stoma; or
  • Colon-in-Continuity (CiC) with documented colonoscopy performed during Screening and which does not give rise to any safety concerns; and
  • Able to separate stool and urine during the 48 hours measuring intervals.
    • Note: A colonoscopy performed within 6 months prior to Screening and not giving rise to any safety concerns is accepted. For patients with a remnant colon, which is not connected to the passage of foods and is thereby dormant, a computerized tomography (CT) scan or magnetic resonance imaging (MRI) (if standard of care at site) will suffice at the discretion of the investigator.

• More than 2 SBS-related or PS-related hospitalizations within 6 months prior to Screening. No SBS-related hospitalizations within 30 days prior to randomization. 
• Poorly controlled inflammatory bowel disease that is moderately or severely active or fistula interfering with measurements or examinations required in the trial.
• Bowel obstruction. 
• Known radiation enteritis or significant villous atrophy.
• Cardiac disease defined as:
  • decompensated heart failure (New York Heart Association [NYHA] Class III-IV);
  • unstable angina pectoris; and/or
  • myocardial infarction within the last 6 months prior to Screening. 
• Clinically significant abnormal ECG.
• Repeated (2 or more consecutive measurements separated by at least 15 minutes) systolic blood pressure measurements > 180 mm Hg.
• Human immunodeficiency virus positive, acute liver disease, or unstable chronic liver disease. 
• Any history of colon cancer. History of any other cancers unless disease-free state for at least 5 years.
• Estimated creatinine clearance (CLcr; by the Cockcroft-Gault formula) < 30 mL/min.
• Hepatic impairment defined as:
  • Total bilirubin ≥ 2 × the upper limit of normal (ULN); or
  • Aspartate aminotransferase (AST) ≥ 5 × ULN; or
  • Alanine aminotransferase (ALT) ≥ 5 × ULN.
• Use of GLP-1, GLP-2, human growth hormone (HGH), somatostatin, or analogs thereof, within 3 months prior to Screening.
• Use of dipeptidyl peptidase (DPP)-4 inhibitors within 3 months prior to Screening.
• Systemic immunosuppressive therapy that has been introduced or has been unstable within 3 months prior to Screening.
• Unstable biological therapy (e.g., anti-TNF-α, natalizumab, etc.) within 6 months prior to Screening, including significant changes in doses or switch of drug.
• Females of childbearing potential, who are pregnant, breast-feeding, intend to become pregnant or are not using highly effective contraceptive methods. 
• Known or suspected hypersensitivity to glepaglutide or related products.
• Previous exposure to glepaglutide.
• Previous participation (randomization) in this trial.
• Current, or within 30 days prior to Screening, participation in another interventional clinical trial that includes administration of an active compound.
• Mental incapacity or language barriers which preclude adequate understanding or cooperation, or unwillingness to comply with trial requirements.
• Any condition or disease or circumstance that in the Investigator's opinion would put the patient at any undue risk, prevent completion of the trial, or interfere with the analysis of the trial results.
• Committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
• An employee of the sponsor or Investigator or otherwise dependent on them.

• Entry and completion of Study M16-067. Completion includes the final endoscopy of Study M16-067. If the final endoscopy for Study M16-067 is missing during the COVID-19 pandemic due to local regulation prohibiting endoscopy, subjects may be allowed to enroll in Substudy 3 should they meet clinical response. 
• Achieved clinical response, defined as decrease in Adapted Mayo Score ≥ 2 points and ≥ 30% from Baseline, PLUS a decrease in RBS ≥ 1 or an absolute RBS ≤ 1 at the last visit of Study M16-067. For subjects with missing final endoscopy for Study M16-067 due to COVID-19 pandemic, clinical response is defined as a decrease in Partial Adapted Mayo Score ≥ 1 point and ≥ 30% from Baseline, PLUS a decrease in RBS ≥ 1 or an absolute RBS ≤ 1 at the last visit of Study M16-067.
• If female, subject must meet the criteria as stated in Contraception Recommendations.
• Subject must be able and willing to give written informed consent and to comply with the requirements of this study protocol, including self-administration or care-giver administration of SC injections. In Japan, if the subject is < 20 years old, a subject's parent or legal guardian must be willing to give written informed consent.

• Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study. Subjects should not be enrolled in Study M16-066 if high grade colonic dysplasia or colon cancer is discovered at the endoscopy performed at the final visit of Study M16-067. 
• Subject who has a known hypersensitivity to risankizumab or the excipients of any of the study drugs or the ingredients of CHO, OR had an AE during Study M16-067 that in the Investigator's judgment makes the subject unsuitable for this study.
• Confirmed positive urine pregnancy test at the Final Visit of Study M16-067.
• Subject is not in compliance with prior and concomitant medication requirements throughout Study M16-067.
• Subject with any active or chronic recurring infections based on the Investigator's assessment makes the subject an unsuitable candidate for the study. 
• Have a known history of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.

Inclusion Criteria:

• Adult male or female ≥ 12 years of age at the time of informed consent or assent.
• Each subject and/or their parents or legal guardian (for adolescents), must read, understand and provide consent or assent together with their parent(s) or guardian signature (for adolescents) on the ICF for this study and be willing and able to adhere to study-related treatment regimens, procedures and visit schedule.
• Diagnosis or presumptive diagnosis of EoE that is confirmed during the Screening period by histology that demonstrates ≥ 15 peak eos/HPF. In order to ensure that a diagnosis can be made, at least 6 biopsies should be taken from both proximal and distal specimens (at least 3 each). Mid-esophageal biopsies are not required (optional). HPF will be defined as a standard area of 235 square microns in a microscope with 40x lens and 22mm ocular:
  • Esophagogastroduodenoscopies and biopsies are to be obtained during the Screening period;
  • Biopsies will be read by a central pathologist;
  • Esophagogastroduodenoscopies and biopsies performed outside the study will not be accepted to meet eligibility criteria;
  • Optional biopsies may be taken and processed locally for local use, only where specified in the local ICF. If serious pathology is unexpectedly encountered biopsies of such lesions must be processed locally.
• Have a subject-reported history of ≥ 6 episodes of dysphagia in the 14 days prior to baseline.
• Completion of the daily diary on at least 11 out of the 14 days during the 2-week Baseline Symptom Assessment.

• Have known contraindication, hypersensitivity, or intolerance to corticosteroids.
• Have a contraindication to, or factors that substantially increase the risk of, EGD procedure or esophageal biopsy or have narrowing of the esophagus that precludes EGD with a standard 9 mm endoscope.
• Have history of an esophageal stricture requiring dilatation within the previous 12 weeks prior to Screening.
• Bone age more than 12 months behind chronological age for adolescent subjects.
• Have any physical, mental, or social condition or history of illness or laboratory abnormality that in the Investigator’s judgment might interfere with study procedures or the ability of the subject to adhere to and complete the study or increase the safety risk to the subject such as uncontrolled diabetes or hypertension or may increase risk of corticosteroid toxicity (e.g., abnormal bone mineral density).
• History of recurrent or current oral or esophageal mucosal infection due to inhaled or nasal corticosteroids.
• Have any mouth or dental condition that prevents normal eating.
• Have any condition affecting the esophageal mucosa or altering esophageal motility other than EoE, including erosive esophagitis (grade B or higher as per the Los Angeles Classification of Gastroesophageal Reflux Disease;21, hiatus hernia longer than 3 cm, Barrett’s esophagus, and achalasia.
• Use of systemic (oral or parenteral) corticosteroids within 60 days before Screening, use of swallowed corticosteroids within 30 days before Screening.
• Initiation of either inhaled or nasal corticosteroids or high-potency dermal topical corticosteroids within 30 days before Screening
• Use of calcineurin inhibitors or purine analogues (azathioprine, 6-mercaptopurine) in the 12 weeks before Screening.
• Use of potent cytochrome P450 (CYP) 3A4 inhibitors (eg, ritonavir and ketoconazole) in the 12 weeks before Screening.
• Initiation of an elimination diet or elemental diet within 30 days before Screening (diet must remain stable after signing ICF).
• Morning (07:00 to 09:00, or as close to that window as possible) serum cortisol level ≤ 5 μg/dL (138 nmol/L) that is not responsive to ACTH stimulation: defined as a serum cortisol level < 16 μg/dL (440 nmol/L) at 60 minutes with ACTH stimulation test using 250 μg cosyntropin administered intramuscularly (i.e., an abnormal result on the ACTH stimulation test).
• Use of biologic immunomodulators in the 24 weeks before Screening (allergy desensitization injection or oral therapy is allowed as long as the course of therapy is not altered during the study period).
• Subjects who have initiated, discontinued, or changed dosage regimen of histamine H2 receptor antagonists, antacids or antihistamines, leukotriene inhibitors or sodium cromolyn within 4 weeks before qualifying endoscopy. If already receiving these drugs, the dosage must remain constant throughout the study.
• Subjects who have changed dosage regimen of PPIs within 8 weeks before qualifying endoscopy. If already receiving PPIs, the dosage must remain constant throughout the study.
• Infection with hepatitis B, hepatitis C, or human immunodeficiency virus.
• Have gastrointestinal bleeding or documented active peptic ulcer within 4 weeks prior to Screening or entering a new study period.
• Have chronic infection such as prior or active tuberculosis, active chicken pox or measles or absence of prior measles, mumps and rubella vaccine. Subjects with tuberculosis exposure or who live in high endemic areas should be assessed locally for tuberculosis before consideration for the study.
• Immunosuppression or immunodeficiency disorder.
• Current malignancy or malignancy within 3 years of Screening. Subjects in remission for at least 3 years post-treatment may be enrolled.
• Known severe bleeding disorder.
• Have a history or presence of Crohn’s disease, celiac disease, or other inflammatory disease of the gastrointestinal tract, including eosinophilic gastroenteritis.
• Have current drug abuse in the opinion of the Investigator.
• Have current alcohol abuse in the opinion of the Investigator.
• Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the study.
• Sexually active females of childbearing potential who do not agree to follow highly effective contraceptive methods through the End of Study visit.
• Have received an investigational product, as part of a clinical trial within 30 days (or 5 halflives, whichever is longest) of Screening. Subjects who are currently participating in observational studies or enrolled in patient registries are allowed in this study.
• Have participated in a prior study with investigational product APT-1011.

• Subject has multiple myeloma, 18 years of age or older and subject or legally authorized representative is able to sign the informed consent form.
• Subject had a subject-specific batch of idecabtagene vicluecel manufactured intended for commercial treatment; however, the final manufactured product was nonconforming and did not meet commercial release criteria. The Sponsor has determined that the nonconforming idecabtagene vicleucel may be released for use under the Expanded Access Protocol.
• Remanufacturing is deemed not feasible or clinically inappropriate per assessment of the treating physician in discussion with the subject.
• Subject is clinically stable, has recovered from any prior toxicities prior to receiving lymphodepleting chemotherapy, and has adequate bone marrow function to receive lymphodepleting chemotherapy.
• Females of childbearing potential must:
  • Have a negative pregnancy test as verified by the treating physician within 7 days prior to the first dose of lymphodepleting chemotherapy following institutional testing methodology practices. This applies even if the subject practices true abstinence from heterosexual contact;
  • Either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, effective contraception without interruption. Contraception methods must include 1 highly effective method from screening until at least 12 months after the lymphodepleting chemotherapy;
  • Agree to abstain from breastfeeding during study participation and for at least 12 months following lymphodepleting chemotherapy;
  • There are insufficient exposure data to provide any recommendation concerning the duration of contraception and the abstaining from breastfeeding following treatment with nonconforming idecabtagene vicluecel. Any decision regarding contraception and breastfeeding after infusion should be discussed with the treating physician.
• Male subjects must:
  • Practice true abstinence or agree to use a condom;
  • There are insufficient exposure data to provide any recommendation concerning the duration of contraception following treatment with nonconforming idecabtagene vicluecel. Any decision regarding contraception after infusion should be discussed with the treating physician.
• Subject must agree to not donate blood, organs, tissue, sperm or semen and egg cells for usage in other individuals for at least 1 year following lymphodepleting chemotherapy. There are insufficient exposure data to provide any recommendation concerning the duration of refraining from tissue donation following treatment with nonconforming idecabtagene vicluecel. Therefore, participants treated with nonconforming idecabtagene vicluecel should not donate blood, organs, tissues, and cells for transplantation.

• Subject has a hypersensitivity to the active substance or to any of the excipients.
• Subject should not experience a significant worsening in clinical status that would, in the opinion of the treating physician, either increase the risk of AEs associated with lymphodepleting chemotherapy or exclude them from treatment with nonconforming idecabtagene vicluecel.
• Subject has any significant medical condition, laboratory abnormality, or psychiatric illness, sociologic or geographic condition that would prevent the subject from participating in the Expanded Access Protocol, complying with protocol requirements or confound the ability to interpret the data in the Investigator's judgement.
• Subject has any condition and/or laboratory abnormality that places the subject at unacceptable risk if he/she were to participate in the Expanded Access Protocol based on the Investigator's judgement.
• Pregnant or nursing women or has intention of becoming pregnant during the study.

• Must be ≥21 years of age.
• Must be approved for DBS surgery at Mayo Clinic for treatment of essential tremor.
• Competent and willing to provide signed, informed consent to participate in the study.
• Stable dose of tremor medications, if applicable, for 30 days prior to study entry.
• Stable dose of antidepressant medications, if applicable, for 90 days prior to study entry.
• Willing to comply with study protocol requirements including:
  • Remaining on a stable dosage of tremor and antidepressant medications, if applicable, during the duration of the study;
  • No significant alcohol or caffeine consumption within 8 hours of study visits;
  • No usage of the Cala TWO device within 8 hours of study visits;
  • Women of child-bearing potential must be willing to have a pregnancy test within 48 hours of the optional PET/CT exams.
• Competent and willing to provide written, informed consent to participate in the study.
• To be enrolled in the optional PET/CT study the subject must be enrolled in the Cala TWO study and meet all of the inclusion criteria and none of the exclusion criteria of that study.

• Moderate to severe ethanol dependence as defined by the criteria outlined in the DSM-5 (score of 4 or higher).
• Implanted electrical medical device, such as a pacemaker, defibrillator, or deep brain stimulator.
• Previous thalamotomy procedure, including stereotactic thalamotomy, gamma knife radiosurgical thalamotomy, and focused ultrasound for the treatment of tremor.
• Suspected or diagnosed epilepsy or other seizure disorder.
• Swollen, infected, inflamed areas, or skin eruptions, open wounds, or cancerous lesions of skin at stimulation site (wrist).
• Peripheral neuropathy affecting the tested upper extremity.
• Presence of any other neurodegenerative disease like Parkinson plus syndromes suspected on neurological examination. These include: multisystem atrophy, progressive supranuclear palsy, dementia with Lewy bodies, and Alzheimer’s disease.
• Anyone suspected to have the diagnosis of idiopathic Parkinson’s disease (PD). This includes excluding anyone with the presence of parkinsonian features including bradykinesia rigidity, or postural instability. Subjects who exhibit only mild resting tremor but no other symptoms or signs of PD may be included.
• Botulinum toxin injection for hand tremor within 6 months prior to study enrollment.
• Are participating or have participated in another interventional clinical trial in the last 30 days which may confound the results of this study, unless approved by the Principal Investigator.
• Significant alcohol or caffeine consumption within 8 hours of study enrollment, which may confound the results of the study, where significant caffeine is considered more than 95 mg (equivalent to a cup of coffee), and significant alcohol is considered more than 14 g (equivalent to 5 oz of wine, 12 oz of beer, or 1.5 oz of distilled spirits).
• Subjects unable to communicate with the investigator and staff.
• Any health condition that in the investigator's opinion should preclude participation in this study.
• Pregnancy or anticipated pregnancy during the course of the study.
• Subjects will excluded from the optional PET/CT study if they have one or more of the following conditions:
  • Subjects unable to lie down without moving for 15 minutes;
  • Subjects whose glucose tests >=200 mg/dL prior to the PET/CT exams;
  • Women of child-bearing potential showing a negative pregnancy test within 48 hours of the PET exams;
  • Claustrophobic patients unable to tolerate the PET/CT scans (no sedation can be offered).

Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this
study:
1. At the time of randomization, requires supplemental oxygen ≥2 LPM due to hypoxemia.
Hypoxemia can be defined by meeting at least one of the following criteria:
 
•SpO2 <92% on or off supplemental oxygen
  - Respiratory failure necessitating mechanical or non-invasive ventilation (CPAP or Bi-PAP)
  - Written declaration from Investigator that subject is clinically hypoxemic and removal of oxygen supplementation would not be considered clinically appropriate for the purpose of measuring SpO2 while on room air
   Note: Documentation of hypoxemia prior to or during the most recent oxygen supplementation must be available in source.
   Note: Subjects who also require invasive mechanical ventilation (MV) or non-invasive positive pressure ventilation (CPAP or bi-PAP) are eligible, although ventilator support is not mandatory
2. Immunocompromised, as defined by one or more of the following:
  - Received an autologous or allogeneic hematopoietic stem cell transplantation (HSCT) at any time in the past
 
•Received a solid organ transplant at any time in the past
  - Has been or is currently being treated with chemotherapy for hematologic malignancies (e.g., leukemia, myeloma, lymphoma) and/or solid tumor malignancies (e.g., lung, breast, brain cancer) at any time in the past
 
•Has an immunodeficiency due to congenital abnormality (only applicable to subjects age < 18 years old) or pre-term birth (only applicable to subjects age ≤ 2 years old)
3. Has, within 3 days prior to randomization, a confirmed LRTI with a sialic acid dependent respiratory virus (SAD-RV, see definition). This can be confirmed by:
 
•bronchoalveolar lavage (BAL) positive for SAD-RV
 
•lung biopsy positive for SAD-RV
 
•chest imaging with a new or worsening finding of pulmonary infiltrate, bronchiolitis, or pneumonitis temporally associated with an upper respiratory tract sample (e.g., tracheal aspirate, sputum, nasopharyngeal swab (NPS), nasopharyngeal wash) positive for SADRV
   Note: These requirements can be fulfilled by results from samples and/or chest imaging that are collected/performed locally as per standard of care within 3 days prior to randomization.
   Note: For all subjects, after obtaining informed consent but within 3 days prior to randomization, a separate nasopharyngeal swab sample will be collected and sent to thecentral laboratory for confirmation of a SAD-RV. The results from the central lab analysis are not required to initiate the subject on study treatment.
4. If female, subject must meet one of the following conditions:
 
•Not be of childbearing potential, defined as one or more of the following conditions:
     - Premenarchal
     - Postmenopausal for at least 1 year
     - Surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy;
 
•Be of childbearing potential and meet all of the following criteria:
     - Has a negative urine or serum pregnancy test (beta-human chorionic gonadotropin) at screening
     - Agrees to practice an acceptable method of contraception (or meets criteria for waiving contraception) from screening until at least 30 days after last dose of study medication (see Section 8.10.1 for details)
Additional contraception requirements may need to be followed according to local regulations and/or requirements.
5. Non-vasectomized males are required to practice effective birth control methods (see Section 8.10.1) from screening until at least 30 days after last dose of study medication
6. Capable of understanding and complying with procedures as outlined in the protocol as judged by the Investigator and able to sign informed consent form prior to the initiation of any screening or study-specific procedures. Subjects must have the ability to return to the hospital to comply with required procedures if they are discharged during the study.
   Note: For subjects, including minors and patients with medical incapacity or impaired consciousness such that they are not able to give fully informed voluntary consent, the subjects' legal representative (parent, guardian or surrogate) must sign an institutional review board (IRB)/independent ethical committee (IEC)-approved informed consent document prior to the initiation of any screening or study-specific procedures. Minor subjects must also sign an IRB/IEC-approved assent form unless not required per local and institution regulations
 

 Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1. Subjects may not be on hospice care or, in the opinion of the investigator, have a low chance of survival during the first 10 days of treatment
2. Subjects with Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), or Alkaline Phosphatase (ALP) ≥3x ULN and Total Bilirubin (TBILI) ≥2x ULN
Note: Subjects with ALT/AST/ALP ≥ 3x ULN AND TB ≥2x ULN that have been chronically stable (for >1 year on more than one assessments) due to known liver pathology including malignancy (primary or metastasis), chronic medications, transplantation, or chronic infection will not be excluded
3. Female subjects breastfeeding or planning to breastfeed at any time through 30 days after the last dose of study drug
4. Subjects taking any other investigational drug used to treat pulmonary infection.
5. Psychiatric or cognitive illness or recreational drug/alcohol use that, in the opinion of the principal investigator, would affect subject safety and/or compliance
6. Subjects with known hypersensitivity to DAS181 and/or any of its components

7. Subjects with severe sepsis due to either their baseline SAD-RV infection or a concurrent viral, bacterial, or fungal infection and meet at least one of the following criteria:
   - Has evidence of vital organ failure outside of the lung (e.g., liver, kidney)
   - Requires vasopressors to maintain blood pressure

• Male or female must be ≥ 12 years.
• For adolescent participants only (12-17 years):  body weight > 40kg.
• Histologically confirmed unresectable or metastatic cutaneous melanoma.
• Documentation of BRAFV600 or NRAS mutation in tumor tissue prior to study treatment as determined by local assay or as determined by central pre-screening assessment performed at a Novartis designated laboratory.
• Previously treated for unresectable or metastatic melanoma.

Participants with NRAS mutation

• Participants must have received prior systemic therapy for unresectable or metastatic melanoma with an anti-PD-1/PD-L1 checkpoint inhibitor as a single agent or in combination with anti-CTLA-4, investigational agents, chemotherapy, or locally-directed anti-neoplastic agents.
• Prior checkpoint inhibitor therapy in the unresectable or metastatic setting is not required for participants who have progressed on or within 6 months of adjuvant therapy with a checkpoint inhibitor.
• Prior therapy with T-VEC (talimogene laherparepvec) is allowed and will not be counted as a prior line of systemic therapy.
• A maximum of two prior lines of systemic CPI-containing immunotherapy for unresectable or metastatic melanoma are allowed.  Additional agents administered with a CPI are permitted.
• To rule out pseudo-progression, participants must have documented progressive disease as per iRECIST v1.1 while on/after treatment of with checkpoint inhibitor therapy.  Confirmation is not required for patients who remained on treatment > 6 months.

Patients with BRAFV600 mutant disease

• Participants must have received prior systemic therapy for unresectable or metastatic melanoma with a checkpoint inhibitor (CPI) either/and anti-PD-1/anti-PD-L1 as a single agent or in combination with anti-CTLA-4, investigational agents, chemotherapy or locally-directed anti-neoplastic agents.  Additionally, participants must have received targeted therapy with a RAFi as a single agent or in combination with a MEKi (+/- CPI allowed) as the last prior therapy. 
• Prior checkpoint inhibitor therapy in the unresectable or metastatic setting is not required for participants who have progressed on or within 6 months of adjuvant checkpoint inhibitors.
• Prior therapy with T-VEC (talimogene laherparepvec) is allowed and will not be counted as a prior line of systemic therapy.
• A maximum of two prior lines of CPI-containing systemic therapy for unresectable or metastatic melanoma are allowed.  Additional agents with CPI are permitted.
• A maximum of one line of targeted therapy is allowed, and it must be most recent line of therapy.
• If a participant discontinued targeted therapy for reasons other than disease progression, a switch to another targeted therapy regimen is allowed.
• Participants must have documented progressive disease as per RECIST v1.1 while on/after treatment with targeted therapy. 
• Participants must have a site of disease amenable to repeated biopsies and must be willing to undergo a new tumor biopsy at baseline and during treatment according to the treating institution’s own guidelines and requirements for such procedure. For screening biopsy, exceptions may be made for patients who have undergone a fresh tumor biopsy out of the screening window and have received no intervening therapy, after discussion with the Novartis medical monitor.  Bone metastases are not acceptable as a site for biopsy.

• All primary central nervous system (CNS) tumors or symptomatic CNS metastases that are neurologically unstable.
• Insufficent bone marrow, hepatic renal function at the screening visit.
• Abnormal ECG as determined by the mean of a triple ECG and assessed locally.
• Cardiac disease or cardiac repolarization abnormality.
• Presence of ≥ CTCAE grade 2 toxicity (except alopecia) due to prior anti-cancer therapy.  Grade 2 endocrinopathies being treated with replacement therapy and are no longer symptomatic.
• History of current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).

Eligibility last updated 10/14/21. Questions regarding updates should be directed to the study team contact.

• Female patients ≥ 18 years of age.
• Patients must have a confirmed diagnosis of high-grade serous EOC, primary peritoneal cancer, or fallopian tube cancer.
• Patients must have platinum-resistant disease:
  • Patients who have only had 1 line of platinum based therapy must have received at least 4 cycles of platinum, must have had a response (CR or PR) and then progressed between > 3 months and ≤ 6 months after the date last dose of platinum;
  • Patients who have received 2 or 3 lines of platinum therapy must have progressed on or within 6 months after the date of the last dose of platinum.
  • Note: Progression should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing progression.
  • Note: Patients who are platinum-refractory during front-line treatment are excluded (see exclusion criteria).
• Patients must have progressed radiographically on or after their most recent line of therapy.
• Patients must be willing to provide an archival tumor tissue block or slides, or undergo procedure to obtain a new biopsy using a low risk, medically routine procedure for immunohistochemistry (IHC) confirmation of FRα positivity.
• Patient’s tumor must be positive for FRα expression as defined by the Ventana FOLR1 (FOLR-2.1) CDx assay.
• Patients must have at least one lesion that meets the definition of measurable disease by RECIST v1.1 (radiologically measured by the Investigator).
• Patients must have received at least 1 but no more than 3 prior systemic lines of anticancer therapy, and for whom single-agent therapy is appropriate as the next line of treatment:
  • Adjuvant ± neoadjuvant considered one line of therapy
  • Maintenance therapy (e.g., bevacizumab, PARP inhibitors) will be considered as part of the preceding line of therapy (i.e., not counted independently);
  • Therapy changed due to toxicity in the absence of progression will be considered as part of the same line (i.e., not counted independently);
  • Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance.
• Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
• Time from prior therapy:
  • Systemic antineoplastic therapy (5 half-lives or 4 weeks, whichever is shorter);
  • Focal radiation completed at least 2 weeks prior to first dose of study drug.
• Patients must have stabilized or recovered (Grade 1 or baseline) from all prior therapy-related toxicities.
• Major surgery must be completed at least 4 weeks prior to first dose and have recovered or stabilized from the side effects of prior surgery
• Patients must have adequate hematologic, liver, and kidney functions defined as:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9 /L (1,500/μL) without G-CSF in the prior 10 days or long-acting WBC growth factors in the prior 20 days;
  • Platelet count ≥ 100 x 10^9 /L (100,000/μL) without platelet transfusion in the prior 10 days;
  • Hemoglobin ≥ 9.0 g/dL without packed red blood cell (PRBC) transfusion in the prior 21 days;
  • Serum creatinine ≤ 1.5 x upper limit of normal (ULN);
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN f. Serum bilirubin ≤ 1.5 x ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 x ULN);
  • Serum albumin ≥ 2 g/dL.
• Patients or their legally authorized representative must be willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements.
• Women of childbearing potential (WCBP) must agree to use highly effective contraceptive method(s) in while on study drug and for at least 3 months after the last dose of MIRV or at least 6 months after the last dose of Pac, PLD, or Topo.
• WCBP must have a negative pregnancy test within 4 days prior to the first dose of study drug.

• Patients with endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of the above histologies, or low-grade or borderline ovarian tumor.
• Patients with primary platinum-refractory disease, defined as disease that did not respond to (CR or PR) or has progressed within 3 months of the last dose of first line platinum-containing chemotherapy.
• Patients with prior wide-field radiotherapy (RT) affecting at least 20% of the bone marrow.
• Patients with > Grade 1 peripheral neuropathy per Common Terminology Criteria for Adverse Events (CTCAE).
• Patients with active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and /or monocular vision.
• Patients with serious concurrent illness or clinically relevant active infection, including, but not limited to the following:
  • Active hepatitis B or C infection (whether or not on active antiviral therapy);
  • HIV infection;
  • Active cytomegalovirus infection;
  • Any other concurrent infectious disease requiring IV antibiotics within 2 weeks before starting study drug.
  • Note: Testing at screening is not required for the above infections unless clinically indicated.
• Patients with history of multiple sclerosis or other demyelinating disease and/or LambertEaton syndrome (paraneoplastic syndrome).
• Patients with clinically significant cardiac disease including, but not limited to, any one of the following:
  • Myocardial infarction ≤ 6 months prior to first dose;
  • Unstable angina pectoris;
  • Uncontrolled congestive heart failure (New York Heart Association > class II);
  • Uncontrolled ≥ Grade 3 hypertension (per CTCAE);
  • Uncontrolled cardiac arrhythmias.
• Patients assigned to PLD stratum only:
  • Left ventricular ejection fraction (LVEF) below the institutional limit of normal as measured by echocardiography (ECHO) or multigated acquisition (MUGA) scan.
• Patients with a history of hemorrhagic or ischemic stroke within six months prior to randomization.
• Patients with a history of cirrhotic liver disease (Child-Pugh Class B or C).
• Patients with a previous clinical diagnosis of non-infectious interstitial lung disease (ILD), including noninfectious pneumonitis.
• Patients with required use of folate-containing supplements (e.g., folate deficiency).
• Patients with prior hypersensitivity to monoclonal antibodies.
• Women who are pregnant or lactating.
• Patients with prior treatment with MIRV or other FRα-targeting agents.
• Patients with untreated or symptomatic central nervous system (CNS) metastases.
• Patients with a history of other malignancy within 3 years prior to randomization.
  • Note: does not include tumors with a negligible risk for metastasis or death (e.g., adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin, or carcinoma in situ of the cervix or breast).
• Prior known hypersensitivity reactions to study drugs and/or any of their excipients.
• People who are detained through a court or administrative decision, receiving psychiatric care against their will, adults who are the subject of a legal protection order (under tutorship/curatorship), people who are unable to express their consent, and people who are subject to a legal guardianship order.
• Simultaneous participation in another research study, in countries or localities where this is the health authority guidance.

• Previously untreated active multiple myeloma starting a new treatment for their disease with one of the three established treatment regimens: VRd, DRd, or DVRd.
• No prior treatment for myeloma.
• Not receiving concurrent treatment for another active malignancy.
• No more than 3 months from start of treatment.

• < 18 years of age. 

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 6/21/23. Questions regarding updates should be directed to the study team contact.

• Males and females, at least 40 years of age, capable and willing to provide informed consent
• Patient must have received a diagnosis of COVID-19 infection within the last 24 hours
• Outpatient setting (not currently hospitalized or under immediate consideration for hospitalization)
• Patient must possess at least one of the following high-risk criteria:
  • 70 years or more of age, obesity (BMI ≥ 30 kg/m2)
  • Diabetes mellitus
  • Uncontrolled hypertension (systolic blood pressure ≥150 mm Hg)
  • Known respiratory disease (including asthma or chronic obstructive pulmonary disease)
  • Known heart failure
  • Known coronary disease
  • Fever of ≥38.4°C within the last 48 hours
  • Dyspnea at the time of presentation
  • Bicytopenia
  • Pancytopenia
  • The combination of high neutrophil count and low lymphocyte count
• Female patient is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile, or is of childbearing potential and practicing at least one method of contraception and preferably two complementary forms of contraception including a barrier method (e.g. male or female condoms, spermicides, sponges, foams, jellies, diaphragm, intrauterine device (IUD)) throughout the study and for 30 days after study completion
• Patient must be able and willing to comply with the requirements of this study protocol.

• Patient currently hospitalized or under immediate consideration for hospitalization
• Patient currently in shock or with hemodynamic instability
• Patient with inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic diarrhea or malabsorption
• Patient with pre-existent progressive neuromuscular disease
• Estimated Glomerular filtration rate (eGFR), using the MDRD equation for all subjects being considered for enrollment, with a cut-off of < 30 mL/m in/1.73m2
• Patient with a history of cirrhosis, chronic active hepatitis or severe hepatic disease
• Female patient who is pregnant, or breast-feeding or is considering becoming pregnant during the study or for 6 months after the last dose of study medication
• Patient currently taking colchicine for other indications (mainly chronic indications represented by Familial Mediterranean Fever or gout)
• Patient with a history of an allergic reaction or significant sensitivity to colchicine
• Patient undergoing chemotherapy for cancer
• Patient is considered by the investigator, for any reason, to be an unsuitable candidate for the study.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 5/1/23. Questions regarding updates should be directed to the study team contact.

• Provide written informed consent from subjects, an impartial witness (for a subject who is physically unable to sign the informed consent form, but able to provide his/her consent by some other means [e.g., speaking, nodding, blinking]), or the subject’s legally authorized representative (LAR) (for a subject who lacks capacity to consent for him/herself [e.g., a subject without mental capacity to consent]), prior to beginning any study procedures.
• Cervical spinal cord injury who meet either of the following criteria:
  • AIS A with ISNCSCI neurological level of injury between C4 and C7 (for C4, the subject must have at least 1 point of motor activity within the ZPP inclusive of C5 to T1);
  • AIS B or C with ISNCSCI neurological level of injury between C4 and C7, and UEMS ≤ 28.
• Male and female subjects, age between 18 and 70 years at time of consent.
• Body mass index (BMI) < 40 kg/m^2.
• Acute traumatic spinal cord injury subjects who can receive MT-3921 as soon as possible after the injury, at least within 48 hours from the time of the injury.
• Willing and able to participate in all aspects of the study, including completion of subjective evaluations, attendance at scheduled clinic visits, and compliance with all protocol requirements as evidenced by providing informed consent.
• Both female and male subjects of childbearing potential must agree to use of contraception or abstinence during the study.

• Any concomitant injury that, in the judgement of the Investigator, interferes with the performance, interpretation or validity of neurological examinations (including fractures requiring casts), such as but not limited to multiple spinal cord lesions, brachial/lumbar plexus injury, cauda equina injury or traumatic brain injury defined by a Glasgow Coma Scale (GCS) <14 at time of examination.
• Poly-traumatic Injury as defined by Injury Severity Score (ISS) values > 25 at time of Screening.
• Penetrating spinal cord injuries.
• Complete transection of the spinal cord or spinal cord contusion size > 3 cm determined by MRI.
• Subjects who are highly anticipated to be dependent on long-term mechanical ventilation (e.g., beyond 10-14 days), which would interfere with study procedures including neurological exams.
• Any other significant pre-existing medical conditions prior to spinal cord injury or current conditions that, in the judgement of the Investigator, may increase the risks associated with study participation, and would preclude successful participation in the study.
• Subjects with history of active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV), except for adequately treated hepatitis B (HBV) and hepatitis C virus (HCV) with documentation of sustained virologic response defined as undetectable HCV RNA at least 12 weeks after the end of treatment.
• History of anaphylaxis or significant allergy to any food and medications.
• History or presence of malignancy within the last 3 years prior to screening, except subjects who have been treated successfully with no recurrence for >1 year of basal cell or squamous cell carcinoma of the skin or in-situ cervical cancer.
• Subjects with hereditary fructose intolerance.
• Psychoactive substance use disorder at any time during the 3 months preceding study entry (as defined by Diagnostic and Statistical Manual of Mental Disorders [DSM-5]).
• Participation in any clinical trial of a new chemical entity within 12 weeks prior to Screening.
• Pregnant or nursing women.

Other inclusion and exclusion criteria may apply.

Eligibility last updated 7/22/22 to match clinicaltrials.gov. Questions regarding updates should be directed to the study team contact.

• Subject must have completed protocol AVTX-803-LAD-301.
• Subject must be between 6 months and 75 years old.
• Subject or parent (for subjects under legal age for consent) has provided written informed consent for this study. Additionally, written informed assent has been provided, as appropriate, for minors of older age, per local institutional review board (IRB)/ethics committee (EC) policy and requirements.
• Subject has biochemically and genetically proven LAD II (SLC35C1-CDG).
• Subject is willing and able to comply with the protocol.
• Women of childbearing potential (WOCBP) meeting the criteria below:
  • Non-lactating and has a negative pregnancy test at screening; AND
  • Uses an acceptable double-barrier method of contraception as determined by the investigator or sub-investigator for the duration of the study and 30 days following the last dose of study drug.
• Male subjects must agree to use an acceptable double-barrier method of contraception with their partner as determined by the investigator or sub-investigator for the duration of the study and 30 days following the last dose of study drug.  

• Subject has severe anemia defined as hemoglobin < 8.0 g/dL (< 4.9 mmol/L).
• Subject has impaired renal function as defined by an eGFR < 90 mL/min.
• Subject has known or suspected intolerance or hypersensitivity to fucose or any ingredients of the investigational product.
• In the investigator’s opinion, subject has a history of failure to respond to fucose at adequate dosing.
• In the investigator’s opinion, subject is not able or not willing to comply with the study requirements.
• Subject is pregnant.

Eligibility last updated 7/13/22. Questions regarding updates should be directed to the study team contact.

• Age 18 years old and above.
• Diagnosis of prolactinoma.
• Ability to provide informed consent.

• None.

• Male or female.
• Age > 18 years old.
• Patients who match the criteria for indication of elective open aortic arch replacement or repair:
  • Total arch;
  • Non-total arch.
• Patients who match the criteria for indication of elective complex aortic aneurysm repair has to respect the following conditions:
  • Patients undergoing complex aortic aneurysm open reconstruction with a suprarenal clamp:
    • thoracoabdominal aortic aneurysms Crawford extent I to IV;
    • abdominal aortic aneurysms of juxtarenal, pararenal, or paravisceral type.
  • For endovascular approach:
    • patients with pararenal or thoracoabdominal aortic aneurysms Crawford extent I to IV and known stage III or IV CKD;
    • patients with pararenal or thoracoabdominal aortic aneurysms Crawford extent I to IV and solitary or single functioning kidney and known stage III or IV CKD.
• Patients will be allowed to participate in concomitant endovascular aortic stent-graft trials and prospective cohort studies as long as these do not involve another investigational study drug.

General

• Unwilling to comply with the follow-up schedule.
• Inability or refusal to give informed consent by the patient or a legally authorized representative.
• Pregnant or breastfeeding.
• Subject who takes multivitamins containing vitamin B3 derivatives in a dose > 200 mg/day.

Clinical / Laboratory

• Renal failure defined as eGFR< 15 mL/min/1.73m^2.
• Patients in permanent Renal Replacement Therapy.
• Patients with chronic liver disease: Child-Pugh score class B and C.

Medication

• Patients in chemotherapy scheme.
• Patients taking any immunosuppressant, except for corticosteroids.
• Patients taking any of these well-known P-glycoprotein substrates: digoxin, fexofenadine, indinavir, sirolimus.
  • For some types of P-glycoprotein substrates, subjects will be closely monitored.

Patients with the following genotypes and/or clinical diagnosis:

• POMC/PCSK1/LEPR heterozygous;
• POMC/PCSK1/LEPR compound heterozygous (two different mutations in gene) or homozygous deficiency obesity;
• POMC/PCSK1/LEPR composite heterozygous (two or more mutations in two or more genes) deficiency obesity;
• Smith-Magenis Syndrome (SMS);
• SH2B1 deficiency obesity;
• Chromosomal rearrangement of the 16p11.2 locus causing obesity;
• CPE compound heterozygous or homozygous deficiency obesity;
• Leptin deficiency obesity with loss of response to metreleptin;
• SRC1 deficiency obesity;
• MC4R deficiency obesity;
  • Note: The specific genotype for all patients must be reviewed by the Sponsor prior to study enrollment to confirm that the patient meets Inclusion Criterion #1. In addition, enrollment of patients in some subgroups may be prioritized by the Sponsor in order to ensure enrollment of patients with (1) well described, loss of function genetic mutations, (2) a variety of genetic variants, or (3) genetic variants likely to respond to setmelanotide.
• Age 6 years and above.
• Obese, defined as Body Mass Index (BMI) ≥ 30 kg/m^2 for patients ≥ 16 years of age or BMI ≥ 95th percentile for age and gender for patients 6 up to 16 years of age.
• Study participant and/or parent or guardian is able to communicate well with the Investigator, to understand and comply with the requirements of the study, and is able to understand and sign the written informed consent/assent.
• Female participants of child-bearing potential must be confirmed non-pregnant, and agree to use contraception as outlined in the protocol. Female participants of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation), post-menopausal for at least 12 months (and confirmed with a screening Follicle Stimulating Hormone [FSH] level in the post-menopausal lab range), and failure to have achieved menarche, do not require contraception during the study.
• Female participants of child-bearing potential must be confirmed non-pregnant, and agree to use contraception as outlined in the protocol. Female participants of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation), post-menopausal for at least 12 months (and confirmed with a screening Follicle Stimulating Hormone [FSH] level in the post-menopausal lab range), and failure to have achieved menarche, do not require contraception during the study.
• Male participants with female partners of childbearing potential must agree to a double-barrier method if they become sexually active during the study. Male patients must not donate sperm during and for 90 days following their participation in the study.

• Recent intensive (within 2 months) diet and/or exercise regimen with or without the use of weight loss agents including herbal medications that has resulted in > 2% weight loss.
• Use of any medication that is approved to treat obesity within three months of first dose of study drug (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion).Note: Glucagon-like peptide-1 (GLP-1) receptor agonists may be used up to the dose  approved for the treatment of diabetes mellitus (e.g., liraglutide up to a daily dose of 1.8 mg) as long as:
  • is it not being prescribed for the treatment of obesity;
  • the dose has been stable for at least three months prior to enrollmen;
  • the patient has not experienced weight loss during the previous three months; AND
  • the patient intends to keep the dose stable throughout the course of the study.
• Gastric bypass surgery within the previous six months or any prior gastric bypass surgery resulting in > 10% weight loss durably maintained from the baseline pre-operative weight  with no evidence of weight regain. Specifically, patients may be considered if surgery was  not successful, or resulted in < 10% weight loss compared to pre-operative baseline weight or clear evidence of weight regain after an initial response to bariatric surgery. All patients with a history of bariatric surgery must be discussed with and receive approval from the Sponsor prior to enrollment.
  • Note: Patients who are unable to complete the PHQ-9 or C-SSRS due to significant neurocognitive defects may be enrolled in the study, as long as in the opinion of the Primary Investigator there are no clinical signs or symptoms of suicidal behavior.
• Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe enough to interfere with the study and/or confound the results. Any patient with a potentially clinically significant disease should be reviewed with the Sponsor to determine eligibility.
• HbA1c > 9.0% at Screening
• .Diagnosis of schizophrenia, bipolar disorder, personality disorder, or other psychiatric disorder(s) that the Investigator believes will interfere significantly with study compliance. Neurocognitive disorders affecting ability to consent will not be disqualifying as long as an appropriate guardian able to give consent has been appointed.
• A PHQ-9 score of ≥ 15 or any suicidal ideation of type 4 or 5 on the C-SSRS during Screening, any lifetime history of a suicide attempt, or any suicidal behavior in the last month.
• History of significant liver disease or abnormal liver tests on Screening (i.e., > 1.5 x upper limit of normal [ULN] for alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase, or serum bilirubin).
  • Note: Patients entering the study with SRC1 haploinsufficiency obesity must be evaluated during the Screening Period for hepatic fibrosis by appropriate imaging techniques (e.g., transient elastography or magnetic resonance elastography). Any patient with moderate or greater fibrosis (e.g., the equivalent of a METAVIR score ≥ 2) will be excluded from the study.
  • Note: A patient with a diagnosis of non-alcoholic fatty liver disease (NAFLD) or non- alcoholic steatohepatitis (NASH) may be allowed to enroll in the study, after consultation with the Sponsor. Other significant liver disease, such as cirrhosis, are exclusionary.
• Glomerular filtration rate (GFR) < 30 mL/min at Screening.
• History or close family history (parents or siblings) of skin cancer or melanoma (not   including non-invasive/infiltrative basal or squamous cell lesion), or patient history of ocular- cutaneous albinism.
• Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of a comprehensive skin evaluation performed by a qualified dermatologist during Screening. Any concerning lesions identified during the Screening Period will be biopsied and results known  to be benign prior to enrollment. If the pre-treatment biopsy results are of concern, the patient may need to be excluded from the study.
• Patient is, in the opinion of the Study Investigator, not suitable to participate in the study.
• Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
• Patients previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide.
• Significant hypersensitivity to any excipient in the study drug.
• Inability to comply with QD injection regimen.
• Females who are breastfeeding or nursing.

Eligibility last updated 2/22/23 to match clinicaltrials.gov. Questions regarding updates should be directed to the study team contact.

• Subjects who have entered and completed Study M16-006 or Study M15-991 or Study M15-989.
• Subjects have completed the study M16-006 or M15-991 and have achieved clinical response.
• Main entry criteria for Study M16-006 and Study M15-991:
  • Males and females aged ≥ 18 to ≤ 80 years of age, or minimum age of adult consent according to local regulations, at the Baseline Visit. Where locally permissible ≥ 16 to < 18 years of age who meet the definition of Tanner stage 5 development;
  • Moderately to severely active CD, defined as average daily SF ≥ 4 and/or average daily AP score ≥ 2;
  • Endoscopic evidence of mucosal inflammation (Simple Endoscopic Score for CD [SES-CD], excluding the presence of narrowing component, ≥ 3 as confirmed by a centrally read endoscopy. During the COVID-19 pandemic the final endoscopy post-induction treatment may not be conducted due to local regulation prohibiting endoscopy and subjects may be allowed to enroll in SS 3 should they meet clinical response.
• Main entry criteria for all other subjects:
  • Patients with Crohn's disease, who have successfully completed another AbbVie risankizumab Crohn's disease study.

• Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.
• Subject who has a known hypersensitivity to risankizumab or the excipients of any of the study drugs or the ingredients of CHO, or had an AE during Studies M16-006, M15-991 or M15-989 that in the Investigator's judgment makes the subject unsuitable for this study.
• Subject is not in compliance with prior and concomitant medication requirements throughout Studies M16-006, M15-991 or M15-989.
• Confirmed positive urine pregnancy test at the Final Visit of Study M16-006, Study M15-991 or Study M15-989.
• Have a known history of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.

• Age 13-90 years, male, female, any race/ethnicity.
• At least one-time opioid lifetime exposure.
• Categorized into OUD cases (based on clinical interview DSM-IV or DSM-V criteria) or an exposed control (no OUD diagnosis).

• Inability to speak English.
• Inability or unwilling to provide consent.
• Unwilling to consent to providing bio-specimens to be stored in the biobank for an indefinite amount of time and to be used in future research studies of as yet unknown design.
• Actively psychotic or suicidal.
• Cognitive concerns.

• Written informed consent.
• Subjects who successfully completed all of the treatment period and the follow-up  period in any of the following studies:
  • CQGE031C2302, CQGE031C2303, CQGE031C2202 or  CQGE031C1301.
• Male and female, ages ≥ 18 years of age.
• Willing and able to complete a daily symptom eDiary for the duration of the study and  adhere to the study visit schedule.

• Use of investigational drugs, other than those in use in the preceding studies, at the  time of enrollment.
• Use of omalizumab within 16 weeks of Screening.
• History of hypersensitivity to the study drug ligelizumab or its components, or to  drugs of similar chemical classes.
• New onset or signs and symptoms of any form of chronic urticarias other than CSU  during the preceding studies CQGE031C2302, CQGE031C2303 or CQGE031C2202.  
• Diseases with possible symptoms of urticaria or angioedema.
• Subjects with evidence of helminthic parasitic infection.
• Documented history of anaphylaxis.
• Pregnant or nursing (lactating) women.

Key

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 9/15/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Cognitively Impaired (EOAD and EO-nonAD) Cohorts Only:

• Meets NIA-AA criteria for MCI due to AD or probable AD dementia.
• Have a global CDR score ≤ 1.0.
• Have capacity to provide informed consent (IC) or has a legal authorized representative or guardian who provides IC.
• Age between 40-64 years (inclusive) at the time of consent .
• Must have a study partner (informant) who spends a minimum average of 10 hours per week with the participant (e.g., family member, significant other, friend, caregiver) who is generally aware of the participants' daily activities and can provide information about the participant's cognitive and functional performance. If the participant does not have a study partner who spends 10 face-to-face hours per week, other arrangements for identifying a viable study partner will be granted on a case-by-case basis by the Site PI .
• Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure.
• Not pregnant or lactating. Women must be two years post-menopausal, be surgically sterile, or have a negative pregnancy test prior to each PET scan.
• Fluent in English.

Inclusion Criteria
•Cognitively Normal (CN) Cohort Only:

• Meets criteria for cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living.
• Have a global CDR score = 0.
• Have capacity to provide informed consent.
• Have a Mini-Mental State Exam score between 26-30 (inclusive). Exceptions may be made for participant with less than 8 years of education at the discretion of the Site PI.
• Age between 40-64 years (inclusive) at the time of consent.
• Must have a study partner (informant) who spends a minimum average of 10 hours per week with the participant (e.g., family member, significant other, friend, caregiver) who is generally aware of the participants' daily activities and can provide information about the participant's cognitive and functional performance. If the participant does not have a study partner who spends 10 face-to-face hours per week, other arrangements for identifying a viable study partner will be granted on a case-by-case basis by the Site PI.
• Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure.
• Not pregnant or lactating. Women must be two years post-menopausal, be surgically sterile, or have a negative pregnancy test prior to each PET scan.
• Fluent in English.

Exclusion Criteria
•All (EOAD, EO-nonAD and CN) Cohorts:

• Meets core clinical criteria for non-AD dementia.
• Two or more first degree relatives with a history of early-onset dementia suggestive of autosomal dominant transmission, unless known pathogenic mutations in APP, PSEN1, PSEN2 have been excluded.
• Known mutation in an ADAD gene (APP, PSEN1, PSEN2) or other autosomal dominant genes associated with other neurodegenerative disorders.
• Contraindications to 3T MRI (e.g., claustrophobia, pacemaker, select aneurismal clip, artificial heart valve, select ear implants, select stents incompatible with 3T MRI, metal fragments or foreign objects in the eyes, skin or body, etc.).
• Lifetime medical history of a brain disorder other than the disorder causing dementia except for headache (exceptions are allowed at the discretion of the Site PI
  •e.g., seizure disorder thought to be due to EOAD).
•  MRI scan with evidence of infection or focal lesions, cortical strokes, multiple lacunes (single lacune is allowable unless it meets criteria for strategic lacune affecting cognition).
• Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol (at the discretion of the Site PI).
• Medical radiation exposure will be assessed by the study physician. If the candidate participant has had more than one nuclear medicine study in the prior 12 months, study inclusion will require approval from the PET Core.
• Investigational agents are prohibited 30 days prior to entry.
• Previous enrollment in a therapeutic trial targeting amyloid or tau.
• Participation in other clinical studies with neuropsychological measures, with the exception of participants who are co-enrolled in the NACC Uniform Data Set (UDS) protocol (Note: This criterion is intended to reduce repeat measures effects during neuropsychological testing. Exceptions are allowed at the discretion of the Site PI).
• Lifetime history of schizophrenia spectrum disorders (DSM-5 criteria).
• Current history (in previous 12 months) of DSM-5 diagnosis of mania, bipolar disorder with or without psychotic features.
• Current history (in previous 6 months) of moderate or severe substance abuse (nicotine or caffeine is allowed).
• Suicidal behaviors in the past 12 months or active suicidal ideations.
• Residing in a 24-hour care skilled nursing facility (at the time of screening).
• History of torsades de pointes or taking medications known to prolong the QT interval.
• Corrected QT (QTc) interval ≥ 458 msec in males or ≥ 474 msec in females.
• For optional lumbar puncture procedure only:
  • Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be not clinically significant by the Site PI:
    • Platelet count <100,000/µl; 
    • INR>1.2;
    • Abnormal PT or PTT at screening.
  • Contraindications to the procedure, including but not limited to severe degenerative joint disease, deformity of the spine, history of a bleeding disorder. 
  • Suspected elevated intracranial pressure, Arnold Chiari malformation or mass lesion d. Use of the anticoagulant medications such as but not limited to warfarin, rivaroxaban, dabigatran.
• Deemed ineligible by the Site PI for any other reason.

• Undergone an overnight polysomnogram that was used to diagnose REM Sleep Behavior Disorder.
• 18 years of age or older.
• Capable of providing informed consent using the current IRB approved consent document.

• Known diagnosis of PD, dementia of any type, or MSA,
• RBD associated with narcolepsy or suspected due to another neurological etiology (i.e. non-idiopathic RBD),
• For Lumbar puncture only: Anticoagulant medication or bleeding disorder,
• For Lumbar puncture only: Prior lumbar surgery or procedure that precludes LP.

• Patients must have 5 or more brain metastases as counted on a T1 contrast enhanced MRI obtained ≤ 30 days from randomization (maximum 15 brain metastases).
• Patients must have a pathological diagnosis (cytological or histological) of a non-hematopoietic malignancy.
• The largest brain metastasis must measure < 2.5 cm in maximal diameter. The total tumour volume must be 30 cm3 or less. Lesion volume will be approximated by measuring the lesion’s three perpendicular diameters on contrast-enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g., xyz/2). Alternatively, direct volumetric measurements via slice by slice contouring on a treatment planning software package can be used to calculate the total tumour volume.
• Centre must either have the ability to treat patients with either a Gamma Knife, Cyberknife, or a linear accelerator-based radiosurgery system, or access to a centre at which the trial is open which can treat with using one of these systems.
• Patient must be ≥ 18 years of age.
• Patient is able (i.e., sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French either alone or with assistance. The baseline assessment must be completed within required timelines, prior to randomization.
• Patient must also be able and willing to complete the neurocognitive testing without assistance from family and companions. Because this is one of the primary goals of this study, patients must be fluent in English or French, and fully testable in one of those languages.
• A patient that is able but unwilling to complete the questionnaires will be considered ineligible.
• ECOG performance status 0, 1, or 2.
• Creatinine clearance must be ≥ 30 ml/min within 28 days prior to registration.
• The Neurocognitive Testing examiner must have credentialing confirming completion of the neurocognitive testing training.
• The enrolling facility is credentialed by IROC to perform SRS and HA-WBRT
  •or have access to a centre where these treatments are credentialed and the study is open. The treating centre must have completed stereotactic radiosurgery credentialing of the specific system(s) to be used in study patients. The treating centre must have completed IMRT credentialing of the specific IMRT system(s) to be used in study patients for the purposes of HA-WBRT.
• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate. A similar process must be followed for sites outside of Canada as per their respective cooperative group’s procedures.
• Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
• In accordance with CCTG policy, protocol treatment is to begin within 14 days of patient enrolment.
• Women/men of childbearing potential must have agreed to use a highly effective contraceptive method. A woman is considered to be of "childbearing potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.
• Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumour production of hCG, as seen with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy.

• Pregnant or nursing women.
• Men or women of childbearing potential who are unwilling to employ adequate contraception.
• Inability to complete a brain MRI.
• Known allergy to gadolinium.
• Prior cranial radiation therapy.
• Planned cytotoxic chemotherapy within 48 hours prior or after the SRS or HA-WBRT.
• Primary germ cell tumour, small cell carcinoma, or lymphoma.
• Widespread definitive leptomeningeal metastasis. This includes cranial nerve palsy, leptomeningeal carcinomatosis, ependymal involvement, cranial nerve involvement on imaging, suspicious linear meningeal enhancement, or cerebrospinal fluid (CSF) positive for tumour cells.
• A brain metastasis that is located ≤ 5 mm of the optic chiasm or either optic nerve.
• Surgical resection of a brain metastasis (stereotactic biopsies will be allowed).
• More than 15 brain metastases on a volumetric T1 contrast MRI (voxels of 1mm3 or smaller) performed within the past 14 days, or more than 10 metastases in the case of a non-volumetric MRI.
• Prior allergic reaction to memantine, or hypersensitivity to any excipients of memantine.
• Current alcohol or drug abuse.
• Current use of NMDA antagonists, such as amantadine, ketamine, or dextromethorphan.
• Diagnosis of chronic liver disease/cirrhosis of the liver (e.g., Child-Pugh class B or C).
• Clinically significant untreated or uncontrolled cardiovascular conditions, and/or symptomatic cardiac dysfunction (i.e., unstable angina, congestive heart failure, myocardial infarction within the previous year, cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects, uncontrolled hypertension).
• Current active or uncontrolled urinary tract infections (UTI).
• History of epilepsy or seizures, and not currently taking anti-epileptic medication.
• Any other serious intercurrent illness or medical condition judged by the local investigator to compromise the patients safety, preclude safe administration of the planned protocol treatment, or would not permit the patient to be managed according to the protocol guidelines.
• Patients with architectural distortion of lateral ventricular systems which, in the opinion of the local investigator, makes hippocampal delineation challenging.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 2/21/23. Questions regarding updates should be directed to the study team contact.

Screening

• The participant must be at least 18 years of age at the time of informed consent.
• The participant must provide written informed consent prior to any study procedures.
• The participant must meet diagnostic criteria for Gorlin Syndrome (GS) including major criterion #3a plus 1 additional major criterion or plus 2 additional minor criteria listed below. While not required for study entry, if participant has genetic testing results available at study entry or any time during the study, the testing result will be collected.

Major Criteria

• > 2 histologically confirmed BCCs or 1 for participant under age 20.
• Odontogenic keratocysts of the jaw confirmed histologically.
• ≥ 3 palmar and/or plantar pits seen at the Screening Visit.
• Bilamellar calcification of the falx cerebri present at less than 20 years of age. Fused, bifid, or markedly splayed ribs.
• First degree relative with GS.
• Patched protein 1 (PTCH1) mutation predicted to be of functional significance in normal tissue.

Minor Criteria

• Macrocephaly.
• Congenital malformations including frontal bossing, cleft lip or palate, "coarse face", moderate to severe hypertelorism.
• Skeletal abnormalities detectable clinically: Sprengel deformity, marked pectus deformity, or marked finger syndactyly.
• Skeletal abnormalities detectable radiographically: bridging of the sella turcica; vertebral abnormalities such as hemivertebrae, fusion or elongation of the vertebral bodies; modeling defects of the hands and feet; flame shaped lucencies of the hands or feet.
• Ovarian fibroma.
• Medulloblastoma.
• The participant is willing to have blood collected for safety and PK testing.
• The participant is willing to abstain from application of a non-study topical medication (prescription or over the counter) to face for the duration of the trial. Moisturizers and emollients are allowed. Participant will be encouraged to use their preferred sunscreen with a sun protector factor (SPF) of at least 30 daily on all exposed skin on the face.
• Participants of childbearing potential must agree to use a medically acceptable, highly effective form of contraception for the entire duration of the study including through the follow-up period.
• The participant is willing to forego treatment of BCCs with anything other than the study IP except when the Investigator believes that delay of treatment of a BCC potentially might
  compromise the health of the participant. During the trial, the only allowed form of BCC treatment is surgical.

Screening

• The participant has previously participated in a clinical trial evaluating sirolimus topical gel within the last 5 years.
• Participants with known hypersensitivity to any of the ingredients in the study medication formulation.
• Participants with current, recent (within five half-lives of the experimental drug or if half-life not known, within the past 6 months prior to Day 0), or planned participation in an experimental drug study while enrolled in this study.
• Participants who are pregnant, breastfeeding or planning to become pregnant during the study including through the follow-up period.
• Participants of childbearing potential who are unwilling or unable to comply with contraception measures.
• The participant has any condition or situation which, in the Investigator's opinion, may put the participant at significant risk, could confound the study results, including disease activity, or could interfere significantly with participation in the study.
• Participants deemed by the investigator as unwilling or unable to remain compliant with all tests and procedures, including photographs of their face, if needed, adherence to the study drug administration regimen, and other protocol-required activities.

Baseline

Participants are eligible to be included in the study only if all the following criteria apply at Day 0, Baseline:

• The participant must have had at least a history of 10 BCCs present on the face, scalp, ears and/or neck (clinically diagnosed and/or biopsy confirmed) within 24 months prior to Randomization/Day 0.
• Female participants of childbearing potential must have a negative urine pregnancy test to participate in the study.

Baseline

Participants are excluded from the study if any of the following criteria apply at Day 0, Baseline:

• The participant has > 20 clinically suspicious lesions on the face at time of randomization.
• The participant has used topical or systemic treatment that might interfere with the evaluation of the study IP.  Among these are use of the following:
  • 5-fluorouracil, imiquimod, diclofenac, ingenol mebutate (topical); itraconazole, SUBA-itraconazole (systemic) within the 3 months prior to Day 0;
  • Hedgehog inhibitors (glasdegib, vismodegib, sonidegib, patidegib) systemically within the 6 months prior to Day 0. Topical Hedgehog inhibitors within the 3 months prior to Day 0;
  • Systemic chemotherapy of any kind within 1 year prior to Day 0;
  • Known inhibitors of the mTOR signaling pathway or systemically within 2 months prior to Day 0;
  • Photodynamic therapy (PDT) to target lesions within 3 months prior to Day 0;
  • Nicotinamide orally (500mg/2 time daily) within 3 months prior to Day 0.
• The participant has previously participated in a clinical trial evaluating an investigational product for treatment of BCCs or GS within 3 months prior to Day 0.
• Participants with an ECOG > 2 at Day 0.
• Participants previously treated for invasive cancer within the past 5 years excluding nonmelanoma skin cancer, Stage I cervical cancer, in situ ductal cell carcinoma of the breast, or chronic lymphocytic leukemia (CLL) Stage 0, at Day 0.

Eligibility last updated 5/5/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria 

• Male or female
• Age 40-70 years 
• Females of childbearing potential
  • Must have a negative pregnancy test prior to receiving the study drug 
  • Agree to use adequate contraception (hormonal or barrier method or abstinence) from the time of screening to a period of 1 year following completion of the drug treatment cycle
  • Are defined as premenopausal and not surgically sterilized, or post-menopausal for fewer than 2 years
  • A urine pregnancy test will be performed prior to the administration of the study drug to confirm negative results
    • If the urine pregnancy test is positive, the study drug will not be administered 
    • Will be confirmed by a serum pregnancy test performed at a central clinical laboratory
  • Females becoming pregnant during the study will continue to be monitored for the duration of the study or completion of the pregnancy, whichever is longer
    • Monitoring will include perinatal and neonatal outcome
    • Any SAEs associated with pregnancy will be recorded
  • Females in the multiple-dose cohorts (M50 and M100) who become pregnant during the treatment cycle will not receive their remaining injections
• Chronic (> 3 months), unilaterally symptomatic, primary femorotibial knee osteoarthritis
• Radiographic medial and/or lateral femorotibial knee OA at least Kellgren-Lawrence grade 2 accompanied by definite joint space narrowing as agreed upon by two study co-investigators 
• Previous 6 week or longer trial of one of the following conservative treatments
  • Activity modification
  • Weight loss
  • Physical therapy
  • Anti-inflammatory medications or injection therapy (e.g. cortisone, hyaluronic acid/viscosupplement)
• Able to routinely walk without assistance (e.g. cane, walker) 
• Clinically stable target knee 
• No surgery planned in the target knee for at least 12 months following the last injection 
• Completed general physical evaluation with primary care provider within 12 months of enrollment 
• Fully understanding of the requirements of the study and willingness to comply with the treatment plan, including
  • Fat harvesting
  • Laboratory tests
  • Diagnostic imaging
  • Repeated knee injections/aspirations
  • Arthroscopic examination 
  • Follow-up visits and assessments 
• Can provide written informed consent and complete HIPAA documentation after the nature of the study is fully explained and prior to any study-related procedure

Exclusion Criteria

• Pregnant or nursing, or planning on becoming pregnant during the study period 
• Congenital or acquired malformation of the target knee resulting in significant deformity or leading to problems with the study treatment or analysis of the results 
• Significant malalignment on full length, standing radiographs 
• Orthopedic hardware or implantable devices anywhere in the body, other than dental 
• Surgery on the index knee within 1 year of study enrollment 
• Injections of any into the index knee within 3 months prior to study enrollment 
• Locking, catching, give-away or another major mechanical symptoms of the target knee
• Symptomatic patellofemoral arthritis or chondromalacia in the index knee
• History of intra-articular infection in the index knee 
• History of superficial infection in the index knee within 6 months of study enrollment, or evidence of current superficial infection affecting the index knee 
• History of falls requiring medical attention, or gait instability 
• Clinically significant abnormal hematology (complete blood count with differential), blood chemistry, or urinalysis screening laboratory results, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, creatinine, and CRP 
• Body mass index (BMI) > 40 kg/m2 
• Taking anticoagulant medications (e.g. warfarin, heparin) or clopidogrel (Plavix)
• Taking herbal therapies or supplements within 4 weeks of enrollment or unwilling to avoid use of herbal therapies or supplements until at least 30 days following completion of the study drug treatment cycle (includes, but not limited to chondroitin sulfate, diacerein, n-glucosamine, piascledine, and capsaicin) 
• Taking non-steroidal anti-inflammatory medications (e.g. COX-2 inhibitors) without a stable dosing regimen for at least 4 weeks before baseline evaluation, or anticipating not remaining on a stable dose until at least 30 days following completion of the study drug treatment cycle
• Use of electrotherapy or acupuncture for OA, unless there is a stable regimen for at least 4 weeks before baseline assessment
• Taking anti-rheumatic disease medication (including methotrexate or other antimetabolites) within 3 months prior to study enrollment 
• On chronic, immunosuppressive transplant therapy or having a chronic, immunosuppressive state, including use of systemic steroids/corticosteroids 
• Current tobacco product use, including nicotine patch or other nicotine products
• Systemic inflammatory, rheumatological or connective tissue disorder including but not limited to rheumatoid arthritis, systemic sclerosis, system lupus erythematosus, and Ehlers-Danlos Syndrome 
• Rheumatological or inflammatory disease of the knee or chondrocalcinosis/calcium pyrophosphate disease (CPPD), hemochromatosis, inflammatory arthritis, arthropathy of the knee associated with juxta-articular Paget's disease of the femur or tibia, ochronosis, hemophilic arthropathy, infectious arthritis, Charcot's knee joint, villonodular synovitis, and synovial chondromatosis 
• Ongoing infectious disease, including but not limited to tuberculosis, HIV, hepatitis, and syphilis
• Clinically significant cardiovascular (e.g. history of myocardial infarction, congestive heart failure or uncontrolled hypertension > 90 mmHg diastolic and/or 180 mmHg systolic), neurologic (e.g. stroke, TIA) renal, hepatic, orthopedic (e.g. surgery on other weight bearing joints that will interfere with study, osteoporosis, acute lower body fractures), or endocrine disease (e.g. diabetes) 
• Vascular or neurological disorder affecting the either lower limb 
• History of cancer/malignancy with the exception of adequately treated basal cell or squamous cell carcinoma of the skin not associated with the target knee
• History of blood dyscrasia, including but not limited to anemia, thrombocytopenia, and monoclonal gammopathy 
• Participation in a study of an experimental drug or medical device within 3 months of study enrollment 
• Known allergy to local anesthetics or other components of the study drug 
• Any contraindication to MRI scan according to MRI guidelines, or unwillingness to undergo MRI procedures 
• History of or current evidence of alcohol or drug abuse or dependence, recreational use of illicit drug or prescription medications, or have use of medical marijuana within 30 days of study entry 
• Any illness or condition which, in the investigators' judgement will interfere with the patient's ability to comply with the protocol, compromise patient safety, or interfere with the interpretation of the study results