Trial Title:
Efficacy and Safety of Phentermine/Topiramate in Youth With Hypothalamic Obesity
NCT ID:
NCT06299891
Condition:
Hypothalamic Obesity
Hypothalamic Tumor
Craniopharyngioma
Conditions: Official terms:
Craniopharyngioma
Adamantinoma
Hypothalamic Neoplasms
Obesity
Topiramate
Phentermine
Conditions: Keywords:
Hypothalamic Lesion
Drug Intervention
Hypothalamic Obesity
Phentermine/Topiramate
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Two-center, double-blind (participant and assessor), randomized, parallel-arm
placebo-controlled 28-week clinical trial, comparing changes related to active drug
(Qsymia®) vs. placebo (matched capsules).
Primary purpose:
Treatment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description:
Eligible subjects will be assigned treatment using a sex-stratified permuted-block
randomization (1:1) to drug vs. placebo for 27 weeks with varying block sizes constructed
by the study statistician.
Intervention:
Intervention type:
Drug
Intervention name:
Phentermine / Topiramate Extended Release Oral Capsule [Qsymia]
Description:
To assess safety and maximum tolerated dose as well as efficacy on weight loss of
Phentermine/Topiramate in individuals with hypothalamic obesity.
Arm group label:
Drug Intervention
Intervention type:
Other
Intervention name:
Placebo
Description:
To assess safety and maximum tolerated dose as well as efficacy on weight loss of placebo
treatment in individuals with hypothalamic obesity.
Arm group label:
Placebo
Other name:
Matching blinded placebo capsules
Summary:
Hypothalamic obesity (HO) refers to the substantial weight gain that often complicates
hypothalamic brain tumors. Children with this treatment-recalcitrant form of obesity have
excess rates of metabolic sequelae compared to otherwise healthy children with similar
obesity, and later experience excess mortality related to cardiometabolic disease. In
this pilot trial, our objective is to gather key preliminary data about
phentermine/topiramate (Ph/T) that is FDA-approved for "common" obesity but has never
been tested in HO. The subset of individuals with HO who experience hyperphagia or excess
daytime sleepiness may benefit from the Ph/T-induced decrease in appetite and increase in
alertness.
Preliminary assessments of safety, adverse events, dosing (Aim 1), as well as of efficacy
(% BMI loss, Aim 2) will be made in a 28-week parallel-arm double-blinded Phase 2
placebo-controlled clinical trial in 12-28-year-old individuals with HO.
Detailed description:
STUDY OVERVIEW This is a two-center, double-blind (participant and assessor), randomized,
parallel-arm 28-week clinical phase II trial, comparing changes from pre- to post
treatment in two study arms of active drug (Qsymia®) vs. placebo capsules. Twenty-four
12-28-year-old participants will be randomized 1:1 into the two intervention groups. The
study will have a single central IRB (CHOP).
In this pilot trial, the objective is to gather key preliminary data about
phentermine/topiramate (Ph/T), a promising option containing a sympathomimetic amine (Ph)
combined with an appetite-suppressive epilepsy drug (T) that is FDA-approved for "common"
obesity but has never been tested in HO. The subset of individuals with HO who experience
hyperphagia or excess daytime sleepiness may benefit from the Ph/T-induced decrease in
appetite and increase in alertness. Preliminary assessments of safety and dosing (adverse
events and maximum tolerated dose - Aim 1), as well as of efficacy (% BMI loss - Aim 2)
will be made in a 28-week parallel-arm double-blinded Phase 2 randomized
placebo-controlled clinical trial in 12-28-year-old individuals with HO. The FDA-approved
dose titration will be followed. Other efficacy and mechanistic outcomes will be measured
as well.
Specific Aims:
Aim 1: To assess safety and maximum tolerated dose of Ph/T. Main outcomes:
treatment-emergent adverse events (including any during withdrawal), maximum tolerated
dose (weeks 0 to 28).
Aim 2: To estimate the treatment effect of Ph/T with respect to weight loss in
individuals with HO. Main outcome: % change in BMI (week 0 to 28) in response to Ph/T vs.
placebo.
Study Approach:
Recruitment. Subjects will be required to travel to one of the two research sites
(Seattle WA; Philadelphia PA). Each subject will be treated for 28 weeks plus 1 week of
an appropriate taper in those participants who reached the highest dose at titration.
Participants will be pre-screened for eligibility via medical record review. Once written
informed consent is obtained, eligibility will be confirmed.
Randomization. Eligible subjects will be assigned treatment using a permuted-block
randomization (1:1) to drug vs. placebo for 28 weeks with varying block sizes constructed
by the CHOP study statistician.
Study visits. Each participant will have a screening visit and 5 in-person study visits:
Weeks 1 (baseline), 3, 14, 16, 28 (end of randomized trial). There will be a remote
contact one week (+/- 3 days) after dose initiation and/or dose escalation to assess dose
tolerability. The remote contact at 29 weeks will be performed to assess for any
withdrawal effects and will be done in-person if there are any safety concerns that are
most appropriately assessed in person. Visits at 1 and 28 weeks will be used for main
outcome collection. Interim visits are required for assessment of dose escalation. Weeks
3 and 16 visits could be done remotely to reduce burden, in particular for individuals
traveling from a distance, if participants prefer and have no concerning safety signals.
Participants will be compensated for their time and travel. Efforts will be made to
schedule study appointments at times that will accommodate participants' schedules.
Main outcome for Aim 1: Safety, as assessed by systematic collection of
treatment-emergent adverse events using a safety monitoring uniform report form (SMURF),
with adverse events graded according to Common Terminology Criteria for Adverse Events
(CTCAE) version 5.0.
Secondary outcome for Aim 1: Maximum tolerated dose of Ph/T, as defined by the dose of
Ph/T that the participant is continuing to take at the week 28 visit, reflecting any dose
individualization.
Main outcome for Aim 2: % change in BMI between weeks 1 (baseline) and week 28 (end of
treatment).
Key secondary outcomes for Aim 2 (all assessed as change between weeks 1 and 28):
proportion of participants who achieve at least 2.5% BMI reduction, proportion of
participants who achieve at least 5% BMI reduction, change in fat mass and visceral fat
(as assessed by DXA) from Baseline to Week 28.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Males and Females; Ages 12-28 years (inclusive)
2. History of rapid weight gain related to tumor onset or treatment, as assessed by an
experienced endocrinologist (for example, change in BMI z-score > 0.2 and/or BMI +5%
during the first 6 months following tumor treatment)
3. Obesity (BMI > 95th%ile for age/sex using CDC 2000 reference for under 18; BMI > 30
kg/m2 for 18+ years)
4. Recent evidence of hypothalamic injury by brain MRI with central review; >6 months
status-post definitive therapy (surgery, chemotherapy, or radiation); no major
operations/surgeries planned during the study period.
5. Stable on pituitary replacement* and/or appetite-modulating medications (including
stimulants) for at least 2 months. *Adjustments of less than 25% (<25%) are
permitted to hydrocortisone, growth hormone or thyroid hormone. Sex steroids and
DDAVP are exempt.
6. Post-menarchal females must use a highly effective form of contraception, unless
hypogonadotropic hypogonadism is documented. All participating females will have
pregnancy testing as outlined in the protocol.
7. Participants must be able to communicate well with the investigative team, must
comply with requirements of the study, and be able to provide written informed
consent and/or assent for individuals less than 18y with consent of a parent/legal
guardian.
Exclusion Criteria:
1. Contraindication to Phentermine or Topiramate, as assessed using current package
inserts. Including: History of glaucoma and known hyperthyroidism.
2. Known history of metabolic acidosis, low bicarbonate on screening laboratory (below
lower limit of normal), or clinically significant bone disease requiring medication
(not calcium or vitamin D).
3. Current or recent (<14 days) use of monoamine oxidase inhibitor.
4. Known hypersensitivity to sympathomimetic amines.
5. Clinically significant cardiovascular conditions, as defined as any of the
following: i) elevated blood pressure, defined as >97%ile for age, sex and height
for adult participants abnormal blood pressure is defined as Stage 2 hypertension
(systolic BP > 160 mm Hg or diastolic BP > 100 mm Hg); ii) history of cardiac
arrhythmia or arrhythmia detected on screening ECG; iii) history of heart failure
and/or cardiomyopathy; iv) prolonged QTc interval (QTc > 460 msec), and/or long QT
syndrome phenotype and/or positive genotype for long QT syndrome pathogenic; v)
history of cardiac disease including coronary artery disease.
6. Females who are pregnant, breastfeeding, or planning to become pregnant during the
trial.
7. "Brittle" diabetes insipidus (in the opinion of the referring endocrinologist, e.g.
requiring frequent hospitalizations and/or frequent abnormal sodium values).
8. Diabetes mellitus requiring insulin/secretagogue. HbA1c > 8.5% at Screening.
9. Clinically significant liver disease and/or known severe hepatic impairment. ALT > 3
x Upper Limit of Normal (ULN) AST > 3 x ULN
10. Clinically significant kidney disease. GFR<60 ml/min/1.73m2
11. History of seizure in the 12 months prior to Screening.
12. History of substance abuse, depression of moderate or greater severity, psychiatric
disorder and/or suicidality.
13. History of abdominal surgery including gastric bypass.
14. Current use of supra-physiologic steroids.
15. History of allergy or sensitivity to test agents. Including individuals with known
aspirin allergy or hypersensitivity and/or known allergy to FD&C Yellow No. 5
(tartrazine).
16. Concurrent use carbonic anhydrase inhibitor.
17. New weight management medication (or more than 5% decrease in weight over prior 2
months on any current, stable regimen), new stimulant, and/or investigational
medication within 2 months prior to Screening, and/or plans to initiate new weight
management regimen.
18. Cognitive impairment that, in the opinion of the investigator, precludes
participation in the study.
19. Individuals considered, in the Investigator's opinion, otherwise not suitable to
participate in the study.
Gender:
All
Minimum age:
12 Years
Maximum age:
28 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
The Children's Hospital of Philadelphia
Address:
City:
Philadelphia
Zip:
19104
Country:
United States
Status:
Recruiting
Contact:
Last name:
Kristin Wade
Phone:
267-398-5761
Email:
wadekl@chop.edu
Facility:
Name:
Seattle Children's
Address:
City:
Seattle
Zip:
98101
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Clinton Elfers
Phone:
513-290-5710
Email:
clinton.elfers@seattlechildrens.org
Start date:
August 1, 2024
Completion date:
May 31, 2026
Lead sponsor:
Agency:
Seattle Children's Hospital
Agency class:
Other
Collaborator:
Agency:
Children's Hospital of Philadelphia
Agency class:
Other
Source:
Seattle Children's Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06299891