Clinical trial NCT06535789: Inhaled Insulin vs Rapid-acting Injections for Post-meal Glucose Control in Women With Gestational Diabetes
Official title: The Safety and Efficacy of Rapid Acting Inhaled Technosphere Insulin (Afrezza) Compared With Subcutaneous Insulin to Achieve Pregnancy-Specific Postprandial Targets Among Patients With Gestational Diabetes
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Diabetes, Gestational
Pregnancy Complications
Glucose Metabolism Disorders
Glucose Intolerance During Pregnancy
Keywords: Gestational Diabetes
Inhaled Insulin
Lead sponsor: Jaeb Center for Health Research
Sponsor class: OTHER
Collaborators: name: Mannkind Corporation
First posted: 2024-08-02
Enrollment: 30
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Participants will complete two in-clinic meal sessions, with random assignment to receive either technosphere insulin (TI) or RAA insulin for the first meal and the other insulin for the second meal.
Primary purpose: TREATMENT

Brief summary: Pregnant women aged 18-40 with gestational diabetes (GDM) will take part in this study. We want to see how two different insulin treatments affect their blood sugar after they eat. These women usually use a rapid-acting insulin analog (RAA) that's injected to control their blood sugar before and after meals. They will come to the clinic for two meal sessions. For the first meal, we will randomly decide if they will use the usual RAA insulin or a newer inhaled insulin called technosphere insulin (TI). They will use the other type of insulin for their second meal. After each meal, we will compare their blood sugar levels.

Detailed description: Gestational diabetes mellitus (GDM) affects up to 25% of births globally, and its rates continue to rise each year. Pregnancy is a dynamic time marked by rapid changes in physiology, anatomy, and metabolism that support the growth and development of the fetus. This period can also be vulnerable, as expectant mothers may experience shifts in body perception, food preferences, and physical fitness, which can lead to decreased self-esteem, depression, and anxiety. A diagnosis of GDM often catches women by surprise and may bring feelings of guilt and anxiety about the potential effects on their baby's health. For pregnant individuals unable to meet specific glucose targets through diet and exercise alone, insulin is recommended as the primary treatment. However, transitioning to insulin injections can provoke fear, stress, and discomfort-both emotionally and physically-for many patients. Consequently, some pregnant women opt for oral anti-diabetic medications like metformin or glyburide due to their apprehension about using insulin injections. Both of these drugs pass through the placenta and raise safety concerns, making them secondary choices according to the American Diabetes Association (ADA) and the American College of Obstetricians and Gynecologists (ACOG).

While GDM is typically managed with injectable insulin, inhalable insulin offers a potential alternative. Technosphere® Insulin inhalation powder (TI) is an ultra-rapid-acting insulin administered via oral inhalation using a breath-powered inhaler. It provides an alternative to injectable insulin for prandial glucose control. It consists of recombinant human insulin adsorbed onto fumaryl diketopiperazine (FDKP), a proprietary excipient that, at acidic pH, self-assembles into particles, and polysorbate 80. TI particles have a median diameter of approximately 2 to 2.5 μm, a size appropriate for inhalation into the lung. Following inhalation, Afrezza particles dissolve immediately at the physiologic pH of the lung, and insulin and FDKP are absorbed systemically. After administration of TI in adults, the maximum serum insulin concentration occurs in approximately 12 to 15 minutes (versus 45 to 60 minutes for RAA via subcutaneous route) and returns to near baseline levels in approximately 180 minutes (versus about 5 hours for RAA).

The United States Food and Drug Administration (FDA) approved TI Inhalation Powder and the Gen2 Inhaler (a dry powder device) as Afrezza® to improve blood sugar control in adults aged 18 years and older with diabetes on June 27, 2014. Inhaled TI has proven safe and effective in reducing postprandial (after-meal) hyperglycemia in individuals with Type 1 and Type 2 diabetes. It's important to note that TI units are not equivalent to injectable insulin units; TI's bioequivalent dose has been found to be about twice that of injectable rapid-acting insulin when prescribed for diabetes management.

All insulins, including TI, have a similar label wording with respect to use in pregnancy indicating that studies have not shown an association of insulin and birth defects and that there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy. Insulin, whether subcutaneously administered or inhaled, has not been demonstrated to cross the placenta secondary to its large molecular weight. TI's inert excipient FDKP is not metabolized and is fully excreted from the body with the majority in urine and some in the feces (i.e. for the amount swallowed). Animal studies using subcutaneous administration of carrier particles at 21 times human dosing demonstrated no adverse fertility, teratogenicity, or other developmental outcomes (described in Afrezza label).

TI's optimal dosing, efficacy and risk for hypoglycemia in pregnancy is unknown. Outside of pregnancy, TI has been shown to cause less hypoglycemia than RAA insulin. The dose conversions of TI from RAA therapy have not been characterized in pregnancy to effectively administer across gestation with the dynamic metabolic changes, although insulin resistance is high in the 3rd trimester and dosing is expected to be at least as high as in patients with T2D (\~2X SQ insulin dosing).

The goal of this investigator-initiated randomized crossover trial is to assess the efficacy of TI in lowering PP glycemia and the frequency of hypoglycemia compared with subcutaneous RAA insulin among pregnant individuals with GDM.

Eligibility criteria: Inclusion Criteria

1. Ability to provide informed consent for study participation
2. Age ≥18 years and \<41 years old
3. Singleton pregnancy at 24-34 weeks gestation
4. Diagnosis of GDM via standard 1-step or 2-step criteria
5. Treated with an insulin regimen that includes a RAA bolus of any type for breakfast, with a dose \<20 units
6. Pre-pregnancy or first trimester body mass index (BMI) 25-45
7. Investigator believes that the protocol can be safely conducted by the participant
8. Able to read and speak English

Exclusion Criteria

1. Type 1 diabetes or type 2 diabetes
2. HbA1c ≥ 6.5%, FBG ≥125 mg/dl or 2-hr glucose ≥200 mg/dL on 75g OGTT, or random plasma glucose ≥200 mg/dL (consistent with pre-existing diabetes and not GDM diagnosis)
3. Current use of any non-insulin glucose lowering medication
4. Using TI (Afrezza), regular insulin, or ≥20 RAA units at breakfast (NPH is permissible)
5. Peak expiratory flow \<80% predicted as measured by peak flow meter
6. Recent history of asthma (defined as using any medications to treat asthma within the last year), chronic obstructive pulmonary disease (COPD), or any other clinically important pulmonary disease (e.g., cystic fibrosis or bronchopulmonary dysplasia), or significant congenital or acquired cardiopulmonary disease as judged by the Investigator
7. Smoking (includes cigarettes, cigars, pipes, and/or vaping devices) within 90 days prior to screening
8. History or current diagnosis of lung cancer
9. Current or anticipated use of oral, inhaled or injectable glucocorticoids during the time period of the trial (topical glucocorticoid use is acceptable)
10. Renal or hepatic impairment that in the investigator's judgment poses a safety risk for the study participant
11. Recurrent Level 2 (blood glucose \<54 mg/dL) or Level 3 severe hypoglycemia events
12. Current use of non-cardio-selective beta blockers
13. Being a member of the study team, having a direct supervisor at place of employment who is also directly involved in conducting the clinical trial (as a study Investigator, coordinator, etc.); or having a first-degree relative who is directly involved in conducting the clinical trial

Primary outcomes:
measure: Post-prandial AUC120
timeFrame: 3 hours from start of meal
Secondary outcomes:
measure: AUC >140 mg/dL
timeFrame: 3 hours from start of meal
measure: Excursion from baseline glucose to peak glucose
timeFrame: 3 hours from start of meal
measure: Maximum peak glucose
timeFrame: 3 hours from start of meal
measure: Time to peak glucose
timeFrame: 3 hours from start of meal
measure: Nadir glucose
timeFrame: 3 hours from start of meal
measure: Mean CGM glucose
timeFrame: 3 hours from start of meal
measure: Time with glucose >120 mg/dL
timeFrame: 3 hours from start of meal
measure: Time with glucose >140 mg/dL
timeFrame: 3 hours from start of meal
measure: Glucose ≤140 mg/dL
timeFrame: 1 hour from start of meal
measure: Glucose ≤140 mg/dL
timeFrame: 2 hours from start of meal
measure: Glucose ≤140 mg/dL
timeFrame: 3 hours from start of meal
measure: Glucose ≤120 mg/dL
timeFrame: 1 hour from start of meal
measure: Glucose ≤120 mg/dL
timeFrame: 2 hours from start of meal
measure: Glucose ≤120 mg/dL
timeFrame: 3 hours from start of meal
measure: Time with Glucose in range 63-120 mg/dL
timeFrame: 3 hours from start of meal
measure: Time with Glucose in range 63-140 mg/dL
timeFrame: 3 hours from start of meal
Other outcomes:
measure: Any blood glucose <54 mg/dL
timeFrame: 3 hours from start of meal
measure: Any blood glucose <63 mg/dL
timeFrame: 3 hours from start of meal
measure: Any blood glucose <70 mg/dL
timeFrame: 3 hours from start of meal
measure: Percent time glucose <63 mg/dL
timeFrame: 3 hours from start of meal
measure: Hypersensitivity to inhaled technosphere insulin
timeFrame: From the time of administration of the first Technosphere Insulin (TI) dose during the meal session until the end of the calendar day (11:59 PM) on the day of the TI meal session, assessed for up to 18 hours.
measure: Severe Hypoglycemia events during the clinic meal session
timeFrame: From the time of administration of insulin (either Technosphere Insulin [TI] or RAA, depending on the meal session visit) until discharge from the clinic, assessed up to 5 hours for each meal session.
measure: Severe hypoglycemia events during the study period
timeFrame: From Screening to Study Completion, an average of 10 days
Locations:
city: Santa Barbara
country: United States
facility: Sansum Diabetes Research Institute
state: California
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Campus
state: Colorado
city: New York City
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: Oregon Health and Science University
name: Amy Valent, DO
role: STUDY_CHAIR
References: