Long-term Effectiveness of the Antiobesity Medication Phentermine (LEAP)

• ClinicalTrials.gov Identifier: NCT05176626
• Recruitment Status: Recruiting
• First Posted: January 4, 2022
• Last Update Posted: December 20, 2022
• Sponsor: Wake Forest University Health Sciences
• Collaborators: Johns Hopkins University; Kaiser Permanente; HealthPartners Institute; The University of Texas Health Science Center, Houston; Biomedical Research Institute of New Mexico; WW International Inc.; KVK-Tech, Inc.; National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Wake Forest University Health Sciences

Study Description

Brief Summary:

The purpose of this research study is to understand the long-term effects of the drug phentermine on weight, blood pressure, other health outcomes, and safety. Phentermine has been approved by the US Food and Drug Administration (FDA) for weight management since 1959, but it has not been approved for long-term use (i.e., treatment lasting more than 12 weeks). This trial is designed to learn about the long-term effects of phentermine for up to 2 years because obesity is a chronic disease and expert guidelines recommend long-term use of anti-obesity medications as one treatment option.

Condition or disease	Intervention/treatment	Phase
Obesity; Obesity; Drug; Lifestyle, Healthy	Behavioral: Online Lifestyle Behavioral Therapy; Drug: Phentermine Hydrochloride 8 MG	Phase 4

Detailed Description:

The Long-term Effectiveness of the Anti-obesity medication Phentermine (LEAP) trial, a placebo-controlled, randomized trial, will be conducted at 5 clinical sites across the United States. All participants will be provided with an evidence-based online lifestyle intervention, and participants receiving 24 mg/day of phentermine vs. a placebo for up to 24 months will be compared in an intent-to-treat fashion. The co-primary outcomes of percent weight loss and change in systolic blood pressure at 24 months will be examined. Also, between group changes in drivers of energy balance, including resting metabolic rate, caloric intake, physical activity and dietary composition will be compared. To explore the effects of weight loss on cardiometabolic health, changes in heart rate, hemoglobin A1c, lipids, waist circumference, atherosclerotic cardiovascular disease (ASCVD) risk score, and novel ECG markers of cardiac strain will be compared. Overall adverse event and serious adverse event rate, including rates of incident cardiovascular disease or death, will be measured.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1000 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Blinded, placebo-matched
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Participants, study investigators and research staff, care providers, laboratory staff, and outcomes assessors will be blinded to treatment assignment.
• Primary Purpose: Treatment
• Official Title: Long-term Effectiveness of the Antiobesity Medication Phentermine
• Actual Study Start Date: June 30, 2022
• Estimated Primary Completion Date: September 2025
• Estimated Study Completion Date: September 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phentermine; Participants randomized to active treatment in LEAP will be provided with phentermine hydrochloride 8 mg scored tablets. This formulation of the drug is commercially available and marketed as Lomaira TM.	Behavioral: Online Lifestyle Behavioral Therapy; Participants will receive access to the WW™ digital application for the duration of their participation. The WW™ digital application can be accessed using a smartphone, tablet or personal computer and includes functions such as food journaling, progress charts, lifestyle coaching , ability to manually enter exercise data or link with a fitness tracking device, incentives for behavior change, recipes, and local restaurant recommendations using GPS. Over the course of 12 clinic visits with an obesity provider, participants will be prescribed a dietary plan based on the WW™ app and will be asked to journal dietary intake.; Drug: Phentermine Hydrochloride 8 MG; At the randomization visit, participants will be started on 8 mg PO daily of phentermine or placebo, with a recommendation to take the medication in the morning. They will be provided with detailed instructions on how to increase their dose of study drug over the subsequent weeks. After one week, participants will increase to 16 mg daily. After the second week, participants will further increase their dose to 24 mg daily and at the 1-month in-person follow-up, participants who tolerate the 24 mg dose will be maintained on this as the maximum daily dose for a total of 24 months. For participants who do not tolerate an escalation in medication dose due to side effects, adverse events, and/or elevations in blood pressure and/or heart rate, the study clinician may adjust the dose and/or delay dose escalation. Study clinicians will work with participants to achieve and sustain the maximum dose tolerated.; Other Name: Lomaira
Placebo Comparator: Placebo; Participants randomized to the control arm of LEAP will be provided with placebo tablets consisting of cellulose and corn starch and manufactured to have the same characteristics of the active drug, including size, shape, weight, and sensory perceptions.	Behavioral: Online Lifestyle Behavioral Therapy; Participants will receive access to the WW™ digital application for the duration of their participation. The WW™ digital application can be accessed using a smartphone, tablet or personal computer and includes functions such as food journaling, progress charts, lifestyle coaching , ability to manually enter exercise data or link with a fitness tracking device, incentives for behavior change, recipes, and local restaurant recommendations using GPS. Over the course of 12 clinic visits with an obesity provider, participants will be prescribed a dietary plan based on the WW™ app and will be asked to journal dietary intake.

Outcome Measures

Primary Outcome Measures :

1. Change in body weight (%) [ Time Frame: Baseline to month 24 ]
   The primary outcome for efficacy will be percent weight loss at 24 months of follow-up, relative to body weight (kg) at randomization.
2. Change in Systolic Blood Pressure (mmHg) [ Time Frame: Baseline to month 24 ]
   The primary outcome to address phentermine's impact on a key cardiovascular disease risk factor, blood pressure, will be assessed at 24 months. Staff will measure BP using a standardized protocol with automated BP measurement devices (Omron HEM907XL) and following standard clinical practice guidelines for blood pressure measurement.

Secondary Outcome Measures :

1. Change in resting energy expenditure (REE) / resting metabolic rate (RMR) [ Time Frame: Baseline to month 6; Baseline to month 12; Baseline to month 24 ]
   RMR will be measured via indirect calorimetry using the KORR ReeVue (KORR Medical Technologies, Salt Lake City, UT).
2. Change in cardiac autonomic function [ Time Frame: Baseline to month 3; Baseline to month 6; Baseline to month 12; Baseline to month 24 ]
   Change in cardiac autonomic function will be measured using heart rate variability with electrocardiogram (ECG). Heart rate variability (HRV) and resting heart rate (RHR) are noninvasive measures of cardiac autonomic function.
3. Dependence on study drug (phentermine) [ Time Frame: Month 24 ]
   Dependence on study drug will be assessed using the Severity of Dependence Scale (SDS), a brief 5-item validated measure of psychological dependence that has been used for both illegal drugs of abuse and prescription drugs with concern for addiction potential. The score ranges from 0-15 with a higher score denoting a stronger dependence on the study drug.
4. Change in Systolic Blood Pressure (mmHg) [ Time Frame: Baseline to month 6; Baseline to month 12; Baseline to month 18 ]
   To address phentermine's impact on blood pressure over the course of the study, change in systolic blood pressure will be assessed at 6 months using a standardized measurement protocol with automated BP devices and following standard clinical practice guidelines for blood pressure measurement.

Other Outcome Measures:

1. Incident cardiovascular disease or death [ Time Frame: Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 21, Month 24 ]
   To address the impact of phentermine on cardiovascular disease and total mortality, participant diagnoses, hospitalizations, treatment, and deaths will be tracked via a combination of self-report and tracking within the electronic medical record.
2. Change in body weight (%) [ Time Frame: Baseline to month 6; Baseline to month 12 ]
   To assess the efficacy of phentermine at intervals throughout the study, percent weight loss at 6 and 12 months of follow-up relative to body weight (kg) at randomization will be measured.
3. Change in self-reported physical activity levels [ Time Frame: Baseline to month 6; Baseline to month 12; Baseline to month 24 ]
   The International Physical Activity (IPAQ) short form is a 7-item index that asks respondents the number of days per week and the amount of time per day spent in vigorous- and moderate-intensity activities and walking, during the seven days prior to the visit. Different levels of physical activity are assigned metabolic equivalent (MET) scores based on the Compendium of Physical Activity and, using MET-minutes, can be converted to both continuous and categorical values

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• BMI 30-44.9 kg/m2 or BMI 27-29.9 with weight related comorbidity (including hypertension, prediabetes, type 2 diabetes mellitus, dyslipidemia, nonalcoholic fatty liver disease, treated obstructive sleep apnea, osteoarthritis, low back pain, gastroesophageal reflux disease)
• English-speaking
• Has a smartphone or other device with regular internet access
• Interested in and willing to lose weight as a result of treatment
• Able to take oral medication and willing to adhere to the clinical visit schedule for the trial and lifestyle based treatment regimen throughout the study duration, as recommended by the study clinician
• For females of reproductive potential: use of effective contraception for at least 1 month prior to randomization and agreement to use such a method during study participation and for an additional 8 weeks after the end of study drug administration
• Provision of electronically-signed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study

Exclusion Criteria:

• History of coronary artery, cerebrovascular or peripheral arterial disease including myocardial infarction, unstable angina, revascularization, stroke/TIA, carotid intervention, claudication
• Poorly-controlled blood pressure (>149/94) or elevated heart rate (>110 bpm)
• History of cardiac arrhythmia
• Active / currently-treated hyperthyroidism
• History of glaucoma or been told by an ophthalmologist that you are at high risk for glaucoma
• Heavy alcohol use within the last 6 months (men: more than 4 drinks on any day or more than 14 drinks per week; women: more than 3 drinks on any day or more than 7 drinks per week)
• History of substance use disorder or active use of illicit substances within the last 12 months. Tetrahydrocannabinol (THC)-containing products will not be considered an illicit substance.
• Use of a drug in the monoamine oxidase inhibitor class, currently or within the last 14 days
• Currently pregnant or lactating/breastfeeding; intention to get pregnant in next 24 months; seeking or in active treatment for infertility
• End-stage renal disease on dialysis or CKD class IV or higher (eGFR <30)
• History of valvular heart disease
• Congestive heart failure (any history or current)
• Cirrhosis or symptoms of liver failure in the last 2 years
• Severe pulmonary disease requiring supplemental oxygen
• Quit using nicotine-containing products less than 6 months prior to baseline visit or intention to quit use in the next 2 years
• Use of oral corticosteroids more than 5 days/month in the last 3 months
• Elevated depressive symptoms
• Uncontrolled anxiety symptoms
• Hospitalization for mental illness in the last 24 months
• Diagnosis of dementia or serious mental illness (e.g., schizophrenia, bipolar disorder, severe depression)
• Binge Eating Disorder, Bulimia or Anorexia Nervosa diagnosis or treatment within the last 2 years
• Prior procedure for weight control (including bariatric surgery, devices)
• Use of phentermine, phentermine-containing medication, or anti-obesity medication with similar mechanism of action to phentermine (e.g., phendimetrazine or diethylpropion) in the previous 24 months
• Use of any non-phentermine-containing medications prescribed for weight loss in previous 12 months
• Unstable dose of weight-loss-promoting medications within the last 12 months. Weight-loss-promoting medications are medication prescribed for another condition, but are known to have weight loss effects. Examples would include use of a GLP1 agonist or SGLT2 inhibitor in patients with diabetes; use of topiramate among patients with migraine headaches.
• Use of any stimulant medications in previous 12 months
• Known allergy or intolerance to phentermine or phentermine-containing medication
• Documented or self-reported weight change (gain or loss) of more than 5% of current body weight in the past 3 months
• History of cancer other than non-melanoma skin cancer in the past 5 years
• History of organ transplantation
• Plan to move outside the area in the next two years
• Unable to make changes to diet (e.g., severe food allergies or intolerances; medically necessary aspects of diet incompatible with intervention)
• Already participating in another research study that includes lifestyle changes and/or study medication or has participated in such a study within the last 12 months
• Total body weight that exceeds 400 lbs., precluding use of the digital scale in the lifestyle intervention
• Upper arm circumference that exceeds 50 cm, precluding use of the OMRON HEM 907 XL to measure blood pressure
• Other concern or medical comorbidity that, per discretion of study clinician, would render the participant unfit or unable to safely take part in the 24-month intervention

Contacts and Locations

Contacts

Contact: Beatriz Ospino-Sanchez; (336) 716-6498; bospinos@wakehealth.edu

Contact: Caroline B Young; (336) 713-4061; cblackwe@wakehealth.edu

Locations

United States, California

Kaiser Permanente Southern California; Enrolling by invitation

Los Angeles, California, United States, 90034

United States, Minnesota

HealthPartners Institute; Recruiting

Saint Louis Park, Minnesota, United States, 55416

Contact: Shelly Cook LEAPStudy@HealthPartners.com

Principal Investigator: Stephanie A Hooker, PhD

Sub-Investigator: Jennifer M Vesely, MD

Sub-Investigator: Karen L Margolis, MD

United States, North Carolina

Atrium Health Wake Forest Baptist Weight Management Center; Recruiting

Winston-Salem, North Carolina, United States, 27104

Contact: Beatriz Ospino-Sanchez 336-716-6498 LEAP_Study@wakehealth.edu

Contact: Kaleb Sizemore (336) 716-8747 LEAP_Study@wakehealth.edu

Principal Investigator: Jessica H Bartfield, MD

United States, Texas

UT Center for Obesity Medicine and Metabolic Performance; Recruiting

Bellaire, Texas, United States, 77401

Contact: Angielyn R Rivera 713-486-1350 LEAPStudy@uth.tmc.edu

Principal Investigator: Deborah B Horn, DO

Sponsors and Collaborators

Wake Forest University Health Sciences

Johns Hopkins University

Kaiser Permanente

HealthPartners Institute

The University of Texas Health Science Center, Houston

Biomedical Research Institute of New Mexico

WW International Inc.

KVK-Tech, Inc.

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Kristina H Lewis, MD; Wake Forest University Health Sciences
• Principal Investigator: Jamy D Ard, MD; Wake Forest University Health Sciences
• Principal Investigator: Nicholas M Pajewski, PhD; Wake Forest University Health Sciences

More Information

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT05176626
• Other Study ID Numbers: IRB00079100; UG3HL155801 ( U.S. NIH Grant/Contract )
• First Posted: January 4, 2022
• Last Update Posted: December 20, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Wake Forest University Health Sciences:

weight-loss; lifestyle intervention; phentermine

Additional relevant MeSH terms:

Obesity; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Phentermine; Central Nervous System Stimulants; Physiological Effects of Drugs; Appetite Depressants; Anti-Obesity Agents; Sympathomimetics; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action