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An Exploratory Evaluation of the Safety and Efficacy of Vorinostat in Pitt Hopkins Syndrome

ConditionPitt Hopkins Syndrome
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age3-21
SponsorUnravel Biosciences, Inc.

About this trial

The study is an exploratory evaluation of the safety and efficacy of vorinostat in Pitt Hopkins syndrome. Each patient will be self-controlled in an adapted N-of-1 study design methodology with three treatment arms, including a 4-week placebo phase and two vorinostat dose arms, including every 8 weeks of daily dosing at a low dose of 80mg/m2/day and 8 weeks of a higher dose at 160mg/m2/day.

Key objectives of the study include:

* To confirm the safety and tolerability of oral vorinostat 80mg/m2/day and 160mg/ m2/day dose levels when administered to PTHS patients * To identify the nature and magnitude of treatment response to vorinostat, as measured by changes in clinical and laboratory parameters indicative of trend towards benefit, as well as changes in mRNA expression (transcriptome response) * Provide a data-driven justification for future study design and statistical analysis plan for subsequent clinical studies assessing safety and efficacy of vorinostat in PTHS

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Subjects ≥3 years of age and ≤ 21 years of age at time of screening

Clinical diagnosis of PTHS with documented pathologic mutation in the TCF4 gene

At time of screening, is in a post-regression phase with no degradation of ambulation, hand function, speech or communication skills in the 4 months prior to screening

Has been on a stable regimen of medication or non-pharmacological treatment for at least 4 weeks prior to the baseline visit

Disqualifiers

Has another clinically significant medical condition other than those related to their TCF4 mutation (e.g. diabetes mellitus, cardiovascular disease, renal disease, respiratory disease, hematological abnormalities, malignancy)

Has major surgery planned during the study period

Pregnant or nursing women

Has a history of brain injury, stroke, other cerebrovascular disease or hypoxic-ischemic encephalopathy

Trial design

Design model

Crossover

Treatments tested in this trial

  • Vorinostat (SAHA)

    Drug

    oral suspension

  • Placebo

    Drug

    placebo

Treatment groups

5 Participants
are divided into 3 treatment groups
Group A: Low dose interventional armExperimental treatment 1 intervention
Group B: High dose interventional armExperimental treatment 1 intervention
Group C: PlaceboPlacebo comparator 1 intervention

Trial outcomes

Primary outcomes

1

Frequency of treatment-related adverse events

Treatment-related adverse events coded by MedDRA will be compared qualitatively between low dose treatment, high dose treatment, and placebo groups

Time frame
20 weeks
2

Drug tolerability as measured by number of treatment discontinuations

The number of patients discontinuing treatment due to adverse events will be assessed between low dose treatment, high dose treatment, and placebo groups

Time frame
20 weeks
3

Change in transcriptomic profile from baseline, as measured by RNA-seq (transcriptome biomarker analysis)

Transcriptome biomarker analysis is widely used to assess dynamic changes in biological systems in response to disease processes and applied stimuli, which cannot be captured with genomic sequencing of DNA mutations and variations. Unravel Biosciences has created a proprietary algorithm for analyzing transcriptome data, identifying underlying signatures of disease progression or recovery. The machine learned gene network approach predicted the use of vorinostat based on restoring a transcriptome signature of Rett syndrome toward a healthy state, which was confirmed preclinically and motivated this clinical trial. The same algorithm will be used to assess time-dependent changes in the transcriptome network signature, to evaluate its ability to capture clinical response data and to measure the extent of restoration of a disease signature back to a healthy state in a human relative to pre-clinical models.

Time frame
20 weeks

Secondary outcomes

1

Change from baseline on PTHS-specific Clinical Global Impression Improvement Scale (CGI-I)

7 point Likert scale with 1=very much improved and 7=very much worse

Time frame
20 weeks
2

Change from baseline in PTHS-specific Clinical Global Impression Severity Scale (CGI-S)

7 point Likert Scale; 1=normal, 7=extremely ill

Time frame
20 weeks
3

Change from baseline in the Caregiver Impression of Improvement scale (CareGI-I)

A 5-point Likert scale is used with the following response options: Much Improved (1); Improved (2); Unchanged (3); Worse (4); or Much Worse (5).

Time frame
20 weeks
4

Change from baseline in the Revised Motor Behavioral Assessment (R-MBA)

Each of the 24 assessment items are scored based on observed or recently reported severity/frequency and scored on a five-point Likert scale between 0 and 4, with higher numbers denoting higher levels of severity/frequency.

Time frame
20 weeks

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Unravel Biosciences, Inc.

Lead sponsor

Source ClinicalTrials.gov
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