Safety & Efficacy of AlloRx SC® in PTHS Patients

Study Overview
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Brief Summary
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This study will evaluate the safety of AlloRx Stem Cells® in subjects with Pitt Hopkins syndrome ages 2-45 with a molecularly confirmed pathogenic mutation in TCF4 or 18q deletion including TCF4. Participants will receive mesenchymal stem cells infusions every 3 months for a year with completion of outcome measures to assess the efficacy of the product.

Detailed Description
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This is a phase 1/2, randomized placebo controlled double blinded standard dose study to evaluate the safety and tolerability of AlloRx® stem cells in pediatric patients with a confirmed diagnosis of a TCF4 mutation consistent with haploinsufficiency causing PTHS. Approximately 26 patients (male and female) ages ≥ 2 and≤ 45 years of age with a genetically confirmed diagnosis of Pitt-Hopkins syndrome caused by molecular findings consistent with a pathogenic mutation in the gene TCF4. Written informed consent will be obtained from the patient's parent or legal guardian/ authorized representative (LAR) prior to participation in the study. The study includes screening, baseline, treatment and safety follow up periods. The procedure for intravenous administration is performed under the supervision of clinician with experience caring for patients with PTHS. Each patient will remain inpatient for at least 24 hours after the initial dose of AlloRx, for frequent vital sign monitoring, electrocardiogram (ECG), blood and urine safety tests, and neurologic assessments. Investigators will work closely with the parent/legal guardian to ensure that any signs of discomfort/distress are immediately communicated to study staff. For the administration of the initial dose of study drug in each study cohort, patients will be dosed in a sequential fashion with no more than one patient receiving their first dose of study drug on the same day. An independent data DSMB will review all safety and laboratory data throughout the study on a periodic basis and ad hoc should an SAE occur. The DSMB will also review all available safety data when all patients have received 2 doses of AlloRx and have had at least two weeks of follow-up in order to determine if it is safe to dose the next patient.

Official Title
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Randomized Double Blind Placebo Controlled Study of the Safety & Efficacy of Therapeutic Treatment With AlloRx Stem Cells® in Patients With Pitt Hopkins Syndrome (Phase 1/2 Study)

Conditions
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Pitt Hopkins Syndrome

Intervention / Treatment
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* Biological: AlloRx Stem Cells®
* Other: Placebo control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent from parent(s) or legal guardian(s)/authorized representative(s) (LAR) Documented genetic confirmation of mutation in TCF4, with clinical diagnosis of Pitt Hopkins Syndrome (PTHS) Stable seizure control (defined as clinically stable with no changes in antiepileptic medications or use of rescue medication over the prior 1 month before the screening visit, other than weight associated dose adjustments) Normal renal function with serum creatinine and spot urine protein within normal limits Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, study restrictions, and all study procedures, including intravenous infusion Exclusion Criteria: Any change in medications or diet/supplements intended to treat symptoms of PTHS (e.g., sleeping aids, supplements, cannabidiol products) over the prior 3 months before screening Inability to ambulate independently or with an assistive device or caregiver handhold Any bleeding or platelet disorder Any clinically significant (CS) cardiovascular, endocrine, hepatic, renal, pulmonary, gastrointestinal, neurologic, malignant, metabolic, psychiatric, or other condition that, in the judgment of the Investigator, will pose a safety risk, make the patient unsuitable for participation in, and/or unable to complete the study procedures Any laboratory abnormality, that, in the Investigator's opinion, could adversely affect the safety of the patient, make it unlikely that the course of treatment or follow up would be completed, or impair the assessment of study result Known positive for hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV). Patient is pregnant or lactating Usage of drugs that increase the risk of bleeding (e.g., heparin, low molecular weight heparin, platelet inhibitors). Use of any investigational oligonucleotide and any investigational drugs in the past 6 months Any prior use of gene therapy

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized Placebo Controlled Double Blinded
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention Arm 1<br>AlloRx Stem Cells IV infusion treatment | Biological: AlloRx Stem Cells®<br>* Umbilical cord-derived allogeneic mesenchymal stem cells<br>|
| Placebo Comparator: Intervention Arm 2<br>IV infusion of normal saline | Other: Placebo control<br>* Placebo infusion without mesenchymal stem cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Incidence of adverse events improvement) in one or more areas of ailments related to PTHS | Collection of all adverse events (AEs) | Change from baseline to day 456 (end of study) | 
| Safety: Incidence of serious adverse events | Collection of all serious adverse events | Change from baseline to day 456 (end of study) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in motor function in individuals with PTHS | Ambulation measures by video and wearable device | Change from baseline to day 456 (end of study) | 
| Change in communication abilities in individuals with PTHS. | Observer-Reported Communication Ability Measure (ORCA) | Change from baseline to day 456 (end of study) | 
| Change in sleep habits | Sleep diary | Change from baseline to day 456 (end of study) | 
| Change in gastrointestinal health | Gastrointestinal Health Questionnaire | Change from baseline to day 456 (end of study) | 
| Change in breath holding spells | Diary of breath holding spells | Change from baseline to day 456 (end of study) | 
| Change in cognition | Bayley Scales of Infant Development (BSID-4) | Change from baseline to day 456 (end of study) | 
| Change in adaptive function | Vineland Adaptive Behavioral Scale-3 | Change from baseline to day 456 (end of study) | 
| Change in autistic features | Childhood Autism Rating Scale (CARS) | Change from baseline to day 456 (end of study) | 
| Change in parent assessment of quality of life | Pediatric Quality of Life Questionnaire | Change from baseline to day 456 (end of study) | 
| Change in global clinical status | PTHS-specific Clinical Global Impression Scale | Change from baseline to day 456 (end of study) |