The RETT REVOLUTION trial is a placebo-controlled, single-blinded, exploratory study with patients serving as their own control ("N of 1" trial design) where the safety and efficacy of vorinostat in the treatment of Rett syndrome will be evaluated. Each patient will be self-controlled in an adapted N-of-1 study design methodology by using a 4-week placebo baseline. Vorinostat dose escalation will occur every 8 weeks of daily dosing: placebo, 80mg/m2/day, 160mg/m2/day.
Key study objectives will include:
* To confirm the safety and tolerability of oral vorinostat 80mg/m2/day and 160mg/ m2/day dose levels when administered to typical Rett 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 Rett syndrome
Female subjects ≥6 years of age and ≤ 21 years of age at time of screening
Has typical Rett Syndrome (RTT), based on diagnostic criteria for RTT described in Neul, et.al., 2010
Has documented, disease causing mutation in the MeCP2 gene
At time of screening, is in the post-regression phase with no degradation of ambulation, hand function, speech or communication skills in the 4 months prior to screening
Has another clinically significant medical condition other than those related to MeCP2 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
Crossover
Vorinostat (SAHA)
Drugoral suspension
Placebo
Drugplacebo
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.
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
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.
Change from baseline on the Rett-anchored Clinical Global Impression Improvement Scale (CGI-I)
7 point Likert scale with 1=very much improved and 7=very much worse
Change from baseline in Rett-anchored Clinical Global Impression Severity Scale (CGI-S)
7 point Likert Scale; 1=normal, 7=extremely ill
Change from baseline in Rett Syndrome Behavior Questionnaire (RSBQ)
The 45-item RSBQ is rated on a Likert 2-point scale and consists of eight subscales: general mood, breathing abnormalities, hand behaviors, repetitive face movements, body rocking and expressionless face, night-time behavior, fear/anxiety, and walking/standing, with ratings reflecting severity and frequency of symptoms. A total score, representing the sum of the 45 items (maximum score 90), and 8 subscale scores are obtained. A lower score represents lower symptom intensity.
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.
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