Inflammation, Insomnia, Sleep Disorder, Type 2 Diabetes Mellitus
Conditions
Brief summary
The investigators aim to determine the effect of suvorexant on subjective total sleep time (TST) in suboptimally controlled Type 2 diabetics with chronic insomnia in a randomized placebo-controlled trial for 3 months.
Detailed description
Type 2 diabetes results from a progressive insulin secretory defect on the background of insulin resistance and is a growing pandemic and a leading cause of morbidity and mortality. Sleep disturbance is one of the underappreciated and important features of Type 2 diabetes, and may contribute to the development of the disease. In those with established Type 2 diabetes, there is emerging evidence from cross-sectional studies that sleep disturbance affects glycemic control. Although cross-sectional studies suggest a relationship between sleep disturbance and glycemic control in Type 2 diabetes, causality is best investigated by interventional studies. Suvorexant has a comparatively benign side effect profile compared to many of the hypnotic agents typically prescribed for insomnia. The investigators aim to determine the effect of suvorexant on subjective total sleep time (TST), as well as subjective wake after sleep onset, Insomnia Severity Index, HbA1c levels and insulin sensitivity, inflammatory markers, and other subjective sleep endpoints.
Interventions
DRUGSuvorexant
10-mg or 20-mg Suvorexant capsules
OTHERPlacebo
Matching placebo capsules
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
The participant, investigator, and clinical research coordinator will remain masked throughout the duration of the study. An unmasked research coordinator will be responsible for assessing mid-point outcomes on the sleep diaries and communicating with the pharmacy for re-randomization medication orders.
Intervention model description
Sequential Parallel Comparison Design: subjects will be randomized in a 1:2 ratio to suvorexant 10-20 mg or equivalent placebo for six weeks, followed by re-randomization of placebo non-responders to either suvorexant or placebo in a 1:1 design for six weeks.
Eligibility
Sex/Gender
ALL
Age
25 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Men or women of any ethnic origin 2. Written informed consent is obtained 3. Speaks and writes in English 4. A willingness and ability to comply with study procedures. 5. Age 25-75 years 6. Diagnosis of Type 2 diabetes with suboptimally controlled blood sugar determined by HbA1c \> 6.5% (and \< 10.0%) at both the screening and randomization visits 7. No changes in diabetes medication in the previous month 8. DSM-5 criteria for Insomnia Disorder 9. Score on the Insomnia Severity Index (ISI) measure \>10, indicating at least a moderate level of insomnia symptoms2 10. Report a total sleep time ≤ 6.5 hours and combined sleep onset latency (SOL) and wake after sleep onset (WASO) \> 45 minutes on 7 or more of the 14 nightly sleep logs during both the initial 2-week screening period and the two-week screening run-in period. Combined SOL and WASO does not decrease by more than 50% on the 2-week sleep diary obtained between the screening visit and the randomization visit.
Exclusion criteria
1. Sleep and medical factors: 1. Diagnosis of severe obstructive sleep apnea not using CPAP (can be included if CPAP adherent), or other untreated primary sleep disorders (e.g. narcolepsy, moderate to severe restless legs syndrome) 2. Shift workers 3. Use of hypnotic medications more than twice per week in the past month 4. Unwillingness to not use sedative-hypnotics (other than suvorexant) during the study period 5. Unwillingness to maintain stable diabetes medication during the study unless medically indicated 6. Positive urine toxic screen for any drugs of abuse other than marijuana at Screening Visit 7. HbA1c ≥ 10.0% at either the screening or randomization visit 2. Psychiatric factors: 1. Current major depressive episode, by report and as indicated by the Quick Inventory of Depressive Symptoms-Self Report (QIDS-SR). 2. Subjects with active or unstable major psychiatric disorder, who, in the investigator's judgement, require further treatment. 3. Current alcohol/substance use disorder 3. Medical factors: 1. Renal or hepatic disease judged to interfere with drug metabolism and excretion 2. Pregnant or breastfeeding 3. Malignancy within past 2 years 4. Surgery within past 3 months 5. Neurological disorder or cardiovascular disease raising safety concerns about use of suvorexant and/or judged to interfere with ability to assess efficacy of the treatment 6. Medical instability considered to interfere with study procedures 7. Concomitant medications with drug interaction or co-administration concerns 8. Contraindications or allergic responses to suvorexant 9. History of being treated with suvorexant 4. Lifestyle and other factors: 1. Travel across two time-zones during the week prior to enrollment 2. Greater than 6 cups of coffee per day
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subjective Total Sleep Time | 2 weeks | Total sleep time as reported on daily sleep diaries |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Subjective Wake After Sleep Onset | 2 weeks | Total time awake after sleep onset as reported on daily sleep diaries |
| Insomnia Severity Index | 2 weeks | A validated tool to measure insomnia severity, on a scale of 0-28, with a higher score representing greater insomnia severity. |
Countries
United States
Participant flow
Pre-assignment details
108 participants were enrolled. 36 participants did not meet the eligibility criteria post-enrollment, and thus were not randomized. 3 additional participants were removed from the study prior to randomization due to protocol non-adherence. So, a total of 39 participants who were enrolled were not randomized to the study. 69 participants were randomized, but 2 of them were not treated, leaving a total of 67 participants who were treated.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group Suvorexant: 10-mg or 20-mg Suvorexant capsules | 20 |
| Placebo Responders Placebo: Matching placebo capsules | 7 |
| Placebo Non-responders Re-randomized to Treatment Suvorexant: 10-mg or 20-mg Suvorexant capsules
Placebo: Matching placebo capsules | 16 |
| Placebo Non-responders Re-randomized to Placebo Placebo: Matching placebo capsules
Placebo: Matching placebo capsules | 18 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Covid-19 | 2 | 0 | 0 | 0 | 1 |
| Overall Study | No longer met study criteria | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Non-responders Re-randomized to Treatment | Placebo Responders | Total | Treatment Group | Placebo Non-responders Re-randomized to Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 61.4 years STANDARD_DEVIATION 8.4 | 60.6 years STANDARD_DEVIATION 7.1 | 60.5 years STANDARD_DEVIATION 8.8 | 61.6 years STANDARD_DEVIATION 8.5 | 58.3 years STANDARD_DEVIATION 10.1 |
| Awakenings | 2.1 Number of Awakenings STANDARD_DEVIATION 1.1 | 1.5 Number of Awakenings STANDARD_DEVIATION 0.8 | 2.1 Number of Awakenings STANDARD_DEVIATION 0.5 | 2.4 Number of Awakenings STANDARD_DEVIATION 1 | 2.2 Number of Awakenings STANDARD_DEVIATION 1.2 |
| Beck's Depression Inventory | 12.1 units on a scale STANDARD_DEVIATION 8.3 | 9.4 units on a scale STANDARD_DEVIATION 4.6 | 9.7 units on a scale STANDARD_DEVIATION 6.4 | 8.4 units on a scale STANDARD_DEVIATION 5.1 | 9.3 units on a scale STANDARD_DEVIATION 6.8 |
| Calculated Total Sleep Time | 6.4 Hours STANDARD_DEVIATION 0.7 | 5.6 Hours STANDARD_DEVIATION 0.9 | 5.9 Hours STANDARD_DEVIATION 0.8 | 6.0 Hours STANDARD_DEVIATION 0.8 | 6.2 Hours STANDARD_DEVIATION 0.7 |
| CRP | 5.7 mg/L STANDARD_DEVIATION 8.3 | 8.2 mg/L STANDARD_DEVIATION 7.5 | 6.4 mg/L STANDARD_DEVIATION 8.7 | 6.5 mg/L STANDARD_DEVIATION 8.9 | 6.0 mg/L STANDARD_DEVIATION 10.2 |
| Diabetes Distress Scale | 33 units on a scale STANDARD_DEVIATION 12.7 | 34.1 units on a scale STANDARD_DEVIATION 18.9 | 33.3 units on a scale STANDARD_DEVIATION 13.1 | 31.9 units on a scale STANDARD_DEVIATION 13.2 | 33.3 units on a scale STANDARD_DEVIATION 12.4 |
| Diabetes Quality of Life | 12.1 units on a scale STANDARD_DEVIATION 8.3 | 9.4 units on a scale STANDARD_DEVIATION 4.6 | 9.7 units on a scale STANDARD_DEVIATION 6.4 | 8.4 units on a scale STANDARD_DEVIATION 5.1 | 9.3 units on a scale STANDARD_DEVIATION 6.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 5 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 7 Participants | 56 Participants | 18 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| HbA1c | 7.5 % of total hemoglobin STANDARD_DEVIATION 0.9 | 7.5 % of total hemoglobin STANDARD_DEVIATION 0.9 | 7.6 % of total hemoglobin STANDARD_DEVIATION 0.8 | 7.7 % of total hemoglobin STANDARD_DEVIATION 1 | 7.7 % of total hemoglobin STANDARD_DEVIATION 0.7 |
| Insomnia Severity Index | 17.3 units on a scale STANDARD_DEVIATION 3.1 | 17.3 units on a scale STANDARD_DEVIATION 3.6 | 16.1 units on a scale STANDARD_DEVIATION 3.6 | 14.7 units on a scale STANDARD_DEVIATION 3.2 | 16.8 units on a scale STANDARD_DEVIATION 3.8 |
| Pittsburgh Sleep Quality Index | 2.1 units on a scale STANDARD_DEVIATION 0.5 | 2.3 units on a scale STANDARD_DEVIATION 0.8 | 2.0 units on a scale STANDARD_DEVIATION 0.6 | 1.8 units on a scale STANDARD_DEVIATION 0.4 | 2 units on a scale STANDARD_DEVIATION 0.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 4 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 7 Participants | 55 Participants | 16 Participants | 18 Participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 42 Participants | 16 Participants | 12 Participants |
| Sex: Female, Male Male | 9 Participants | 0 Participants | 19 Participants | 4 Participants | 6 Participants |
| Sleep Efficiency | 82.9 % of time sleeping/time in bed STANDARD_DEVIATION 0.09 | 80.4 % of time sleeping/time in bed STANDARD_DEVIATION 0.03 | 79.2 % of time sleeping/time in bed STANDARD_DEVIATION 0.09 | 75.7 % of time sleeping/time in bed STANDARD_DEVIATION 0.1 | 80.0 % of time sleeping/time in bed STANDARD_DEVIATION 0.09 |
| Sleep Onset Latency | 34.9 Minutes STANDARD_DEVIATION 26.5 | 47.1 Minutes STANDARD_DEVIATION 33.7 | 34.9 Minutes STANDARD_DEVIATION 22.5 | 35.1 Minutes STANDARD_DEVIATION 17.2 | 29.0 Minutes STANDARD_DEVIATION 19 |
| Subjective Total Sleep Time | 6.3 Hours STANDARD_DEVIATION 0.7 | 5.6 Hours STANDARD_DEVIATION 0.9 | 5.9 Hours STANDARD_DEVIATION 0.8 | 5.5 Hours STANDARD_DEVIATION 0.7 | 6.1 Hours STANDARD_DEVIATION 0.7 |
| Wake After Sleep Onset | 64.8 Minutes STANDARD_DEVIATION 42.3 | 73.8 Minutes STANDARD_DEVIATION 41.9 | 76.1 Minutes STANDARD_DEVIATION 44.2 | 88.2 Minutes STANDARD_DEVIATION 50.7 | 73.1 Minutes STANDARD_DEVIATION 46.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 43 | 0 / 20 | 0 / 16 | 0 / 18 | 0 / 7 |
| other Total, other adverse events | 10 / 22 | 2 / 43 | 6 / 20 | 6 / 16 | 0 / 18 | 1 / 7 |
| serious Total, serious adverse events | 1 / 22 | 0 / 43 | 0 / 20 | 0 / 16 | 0 / 18 | 0 / 7 |
Outcome results
Primary
Subjective Total Sleep Time
Total sleep time as reported on daily sleep diaries
Time frame: 2 weeks
Population: Three participants in the placebo group dropped out before any baseline or follow-up data could be collected. An additional 3 participants in the treatment group dropped out and one participant did not complete the sleep diaries, leaving only 19 participants with interpretable data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Group | Subjective Total Sleep Time | 6.4 hours | Standard Deviation 0.8 |
| Placebo Responders | Subjective Total Sleep Time | 7.0 hours | Standard Deviation 0.9 |
| Placebo Non-responders Re-randomized to Treatment | Subjective Total Sleep Time | 6.7 hours | Standard Deviation 0.8 |
| Placebo Non-responders Re-randomized to Placebo | Subjective Total Sleep Time | 6.7 hours | Standard Deviation 0.7 |
p-value: 0.15SPCD analysis
Secondary
Insomnia Severity Index
A validated tool to measure insomnia severity, on a scale of 0-28, with a higher score representing greater insomnia severity.
Time frame: 2 weeks
Population: Three participants in the placebo group dropped out before any baseline or follow-up data could be collected. An additional 3 participants in the treatment group dropped out and one participant did not complete the sleep diaries, leaving only 19 participants with interpretable data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Group | Insomnia Severity Index | 7.1 units on a scale | Standard Deviation 5 |
| Placebo Responders | Insomnia Severity Index | 5.6 units on a scale | Standard Deviation 4.1 |
| Placebo Non-responders Re-randomized to Treatment | Insomnia Severity Index | 10.9 units on a scale | Standard Deviation 5.7 |
| Placebo Non-responders Re-randomized to Placebo | Insomnia Severity Index | 9.1 units on a scale | Standard Deviation 5.4 |
Secondary
Subjective Wake After Sleep Onset
Total time awake after sleep onset as reported on daily sleep diaries
Time frame: 2 weeks
Population: Three participants in the placebo group dropped out before any baseline or follow-up data could be collected. An additional 3 participants in the treatment group dropped out and one participant did not complete the sleep diaries, leaving only 19 participants with interpretable data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Group | Subjective Wake After Sleep Onset | 62.4 minutes | Standard Deviation 49.6 |
| Placebo Responders | Subjective Wake After Sleep Onset | 31.4 minutes | Standard Deviation 21 |
| Placebo Non-responders Re-randomized to Treatment | Subjective Wake After Sleep Onset | 36.7 minutes | Standard Deviation 25.8 |
| Placebo Non-responders Re-randomized to Placebo | Subjective Wake After Sleep Onset | 48.3 minutes | Standard Deviation 30.6 |