Assessing the Safety of Buprenorphine in People With Sickle Cell Disease
Phase: PHASE2
Conditions: Sickle Cell Disease
Sponsor: Johns Hopkins University

Date: May 28, 2020 
Principal Investigator: Sophie Lanzkron 
Application Number: IRB00159636 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessing the Safety of Buprenorphine in People With Sickle Cell Disease 
NCT03492099 
Last updated on: May 28, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. Abstract 
Provide no more than a one page research abstract briefly stating the problem, the research 
hypothesis, and the importance of the research. 
There are only a few therapies available to decrease vaso-occlusive crisis (VOC) in people with sickle cell 
disease; stem cell transplant, chronic transfusion therapy and hydroxyurea.  Most recently L-glutamine 
has been FDA approved but it is reserved for only a small subset of people with the disease. Transplant is 
the only known cure for this disease. Its safety and efficacy, especially in adults, remains a concern and is 
only available to adults as a research protocol. Chronic transfusion therapy is an effective way of 
decreasing the risk of several complications of SCD including stroke and VOC events. Hydroxyurea is an 
effective disease-modifying therapy that decreases the risk of VOC by 50%. However, neither chronic 
transfusions nor hydroxyurea have been shown to decrease the intensity of chronic pain. There is a 
subset of patients who are on effective disease modifying therapy, yet continue to have frequent acute 
visits for parenteral opioids and are maintained on high dose oral opioids as outpatients.  
Buprenorphine is a partial mu-agonist and kappa antagonist and has a very high affinity for the mu 
receptors, with an elimination half-life of 28-37 hours for the sublingual administration. The lower risk for 
misuse, diminished withdrawal symptoms and cravings for opioids as well as the reduced risk of 
overdose in this drug make it an appealing alternative to full agonist opioid use in a subset of patients 
with sickle cell disease on who are unable to wean off of opioids.  
Most relevant to SCD patients on high doses of opioids, there has been recent data on successful 
conversion for patients with chronic pain who are on high-dose opioids, from 100mg to 400mg morphine 
equivalents, to SL buprenorphine. This study reported a decrease in pain scores after the initiation of SL 
buprenorphine therapy for more than two months. Our goals of this study is to assess patient important 
outcomes post conversion to buprenorphine.  
 
 
2. Objectives 
The purpose of this study is to assess the safety and benefit of converting adults with sickle cell disease on 
high dose opioid therapy with evidence of opioid use disorder to buprenorphine. The primary outcome will 
be to assess the safety of the protocol. Secondary outcomes will include measures of acute care utilization 
and health related quality of life after conversion.   
Primary Endpoint: This will be a descriptive study assessing the safety and benefit of converting subjects 
from full agonist opioids to buprenorphine. Data will be collected on need for hospitalization within 72 hours 
of conversion due to withdrawal induced VOC, as well as average COWS scores.  
Secondary Endpoint: Measurement of quality of life, decrease in pain measured by the BPI and Promis pain 
tools decrease acute care utilization.  In addition we will collect data from the 15-20 patients that have 

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already been converted to buprenorphine as part of routine care to formally examine utilization pre and post 
conversion. 
 
3. Background 
Sickle cell disease (SCD) is a genetic disorder of the hemoglobin that leads to severe morbidity and early 
mortality. It is the most common disease detected by newborn screening efforts in the United States (U.S.) 
[1]. Between 80,000 and 100,000 individuals in the U.S. are affected by some form of SCD [2]. African-
Americans (AA) are most affected in the U.S., as 1 per every 400 AA newborns is born with the disease. There 
are several genotypes that lead to similar phenotypes in SCD. Those who are homozygote for the sickle 
mutation (SS) have the most severe form of the disease and typically make up 60-70% of those with sickle 
cell disease. People with SC disease are compound heterozygotes and are considered to have a milder 
phenotype but there is a wide spectrum and chronic pain is quite prevalent in people with SC disease often 
due to avascular necrosis of the hips and shoulders. The damage SCD inflicts on sufferers is dramatic. The 
disease reduces life expectancy by approximately 30 years compared to the general population [3]. 
Furthermore, the disease limits quality of life - as severely as does end-stage renal disease requiring 
hemodialysis [4].  
The best-known complication of SCD is the vaso-occlusive crisis (VOC). These acute, excruciatingly painful 
events are the leading cause of hospital and emergency department utilization [5], and can be associated 
with such lethal and disabling complications as acute chest syndrome and stroke. Triggers for the 
development of VOC include intravascular volume depletion, stress and infection. In addition to these acute 
episodes of pain, the prevalence of chronic pain is very high [6], [7]. Acute and chronic pain and disease 
severity contribute to extraordinarily high levels of unemployment, and decreased productivity in this patient 
population. Therefore, the persistent balance of pain control and quality of life remains a challenge.  
The mechanisms of chronic pain in SCD are poorly understood. A number of factors ranging from genetic to 
behavioral likely regulate the pain response in people with SCD and include interactions between the 
nervous, endocrine, and immune systems [8]. The role of the immune system is of particular interest in 
understanding pain due to SCD; the role of inflammation in acute painful episodes is currently being explored 
through clinical trials investigating new treatment modalities. That ongoing inflammation may play a role in 
chronic pain is suggested by the identification of elevated levels of inflammatory cytokines and substance P, 
the neuropeptide modulator of inflammation and nociception, in SCD [9]. Additionally, chronic pain resulting 
from SCD is now hypothesized to be partly a disorder of central sensitization and peripheral neural 
sensitization. Central sensitization is a complex phenomenon, with contributions from plasticity induced by 
excitatory amino acids via NMDA receptors [10] and neural changes induced by inflammatory mediators and 
other nociceptive chemical messengers. To make things more complicated, our group and others have shown 
that opioid induced hyperalgesia may contribute to chronic pain via central sensitization [11]. A fascinating 
outcome of successful, curative stem cell transplant is that almost every adult patient reported in the 
literature who was on chronic opioid therapy prior to transplant was weaned off of those medications post-
transplant. This phenomenon, which we have seen in our own transplant population, suggests that bone 
damage is likely a small component of the chronic pain and raises even more concern that hyperalgesia 
induced by opioid use itself may be playing a role in the patient experience of chronic pain.  
The current standard of care for the treatment of chronic pain in people with sickle cell disease is the use of 
both long and short acting opiates. Full agonists are opioid drugs that bind completely to mu opioid receptors 
in the brain, and cause them to produce endorphins which relieve pain [12]. The best approach to the 
treatment of chronic pain in people with sickle cell disease is unclear and there is little literature on the 
effectiveness of chronic opioid therapy in this patient population. In a recently published paper we compared 
pain symptoms in 83 adults who were either on chronic opioid therapy or not. We found that those on 
chronic opioid therapy exhibited greater levels of clinical pain, central sensitization as well as higher levels of 
healthcare utilization. This suggested that despite the use of opioid therapy, patients continued to have a 
very high symptom burden.  

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As with any persistent use of opiates for other chronic pain conditions, there is an increase probability of 
opioid dependency and in rare cases, an increased probability of aberrant opioid use. Opioid induced 
hyperalgesia, central sensitization and refractory pain are potential long-term outcomes for many SCD 
patients on long term opioids, potentially leading to higher doses of opioids over time [11]. Therefore, there 
may be great value in reducing the use of full agonist opioids for patients with sickle cell disease.  
There are only three therapies available to decrease vaso-occlusive crisis (VOC); stem cell transplant, chronic 
transfusion therapy and hydroxyurea. Transplant is the only known cure for this disease; its safety and 
efficacy, especially in adults, remains a concern and is only available to adults as a research protocol. Chronic 
transfusion therapy is an effective way of decreasing the risk of several complications of SCD including stroke 
and VOC events [13]. Hydroxyurea is an effective disease-modifying therapy that decreases the risk of VOC by 
50%. However, neither chronic transfusions nor hydroxyurea have been shown to decrease the prevalence of 
chronic pain. There is a subset of patients who are on effective disease modifying therapy, yet continue to 
have frequent acute visits for parenteral opioids and are maintained on high dose oral opioids as outpatients.  
Buprenorphine is classified as a partial mu-agonist and kappa antagonist and has a very high affinity towards 
the mu receptors, with an elimination half-life of 28-37 hours for the sublingual administration [14]. The 
lower risk for misuse, diminished withdrawal symptoms and cravings for opioids as well as the safety profile 
of this drug make it an appealing alternative for full agonist opioid use in a subset of patients with sickle cell 
disease who are unable to wean off of opioids.  
Most relevant to SCD patients on high doses of opioids, there has been recent data on successful conversion 
for patients with chronic pain who are on high-dose opioids, from 100mg to 400mg morphine equivalents, to 
SL buprenorphine. This study reported a decrease in pain scores after the initiation of SL buprenorphine 
therapy for more than two months [14]. Reports of severe withdrawal requiring hospitalization on the day of 
conversion to buprenorphine have been reported. As we have started converting patients as our standard of 
care we will collect data on patient important outcomes to document improved outcomes post conversion.  
 
PRELIMINARY RESULTS  
We have collected preliminary data on 8 patients that we successfully converted from relatively low dose of 
chronic opioid therapy to buprenorphine. Table 1 details patient characteristics and outcomes post 
conversion.  

 
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Table 1: Preliminary results from SCD patients who have successfully converted from chronic opioid therapy to 
buprenorphine. 
Pt ID  Hemoglobin 
Genotype  
Sex  Total opioid 
dose/day 
prior to 
conversion 
(morphine 
milligram 
equivalents)  
Number of 
acute pain 
visits in 6 
months 
prior to 
conversion  
Initial dose of 
Buprenorphine  
Number of 
acute pain 
visits in 6 
months 
post 
conversion  
Complications 
(w/i 72 hours 
of initiation)  
B001  SS  
M  
34.32 mg  
0  
Suboxone 
2mg/0.5mg  
0  
NONE  
B002  SC  
F  
137.28 mg  
2  
Suboxone 
24mg  
2  
Abdominal 
pain/cramping  
B003  SS  
M  
156.52mg  
25  
Zubsolv 
17.1mg/4.3mg  
1  
None  
B004  SS  
M  
45 mg  
32  
Butrans 20mcg  
24  
None  
B005  SS  
M  
34.32 mg  
56  
Zubsolv 
4.2mg/1.08mg  
2  
None  
B006  SS  
F  
90 mg  
22  
Zubsolv 12.6mg  3  
Acute pain  
B007  SS  
M  
90 mg  
11  
Zubsolv 17.4mg  0 
(admitted 
x4 for DKA) 
None  
B008  SS  
M  
96 mg  
7  
Suboxone 8mg  
4  
None  
 
 
4. 
Study Procedures 
Prior to enrolling on this trial participants will have already made a decision to convert to 
buprenorphine therapy after lengthy discussions with the clinical care team. That discussion 
includes risks and benefits of buprenorphine and the need to be in mild- moderate withdrawal 
prior to initiating buprenorphine.  In addition, most patients will be weaned down as much as 
possible from their current opioid dose prior to initiating the protocol below.   
a. 
Study design, including the sequence and timing of study procedures.   
1. Within 90 days prior to day 0 subject will sign Informed Consent Form (ICF) (R) , have urine 
toxicology testing, and complete HRQoL tool (ASCQ-Me) (R),brief pain inventory (BPI) (R), the 
PROMIS Pain Interference – Short Form instrument (R), and the PROMIS Physical Function – 
Short Form instrument (R). The ASCQ-Me tool is a validated health related quality tool for use 
specifically in SCD. The PROMIS Pain Interference instrument measures the degree to which 
pain hinders social engagement and life enjoyment. The PROMIS Physical Function instrument 
measures the degree to which pain affects everyday physical activities.  
2. Data will be collected on acute care utilization, sickle cell disease co-morbidities from chart 
abstraction and recorded in case report forms.  
3. Day 0:   
a. Subject will complete ASCQ-Me, PROMIS Pain Interference, PROMIS Physical Function, 
and BPI with 7 day anchor (R).  
b. Prior to discharge from SCIC subject will have COWS assessment, pain rating collected. 
4. Day 1: Subject will return to repeat COWS. 
5. Subject will return day 14, day 30, day 90, and day 180 to repeat ASCQ-Me, PROMIS Pain 
Interference, PROMIS Physical Function, and BPI (R), or subject will complete these surveys 
over the phone or online on those days in lieu of coming for a study visit. Acute care utilization 
will be collected from subject, medical record and Crisp.  

 
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a. The only change in the ICF version approved by IRB on November 6 2019 was the option of 
completing the study surveys remotely (over the phone or online) for participants. Patients 
that were consented using a previous version of the ICF and are enrolled to the study 
before the November version, have agreed to all study procedures, but have not agreed to 
having the option to complete the study surveys online or over the phone. The study team 
will reach out to these currently enrolled patients during in-person clinical visits, via 
telemedicine appointments or over the phone to re-consent them to the study in-person or 
remotely using the ICF version approved on November 6 2019. On the instances when the 
re-consent  process is done remotely, the person obtaining the re-consent will: 
i. Sign, print their name, and add date and time of the re-consent, under the consenter 
line. 
ii.  Add on the line of the patient signature: [First and Last name of patient] provided 
verbal affirmation of this newer version of their previously signed consent (the only 
change from previous signed version by patient is that the surveys can be completed 
remotely). 
6. Data will be extracted from EPIC and CRISP on health care utilization for the 6 months prior to 
enrollment and 3 years post conversion. 
7. We will also collect data on the 15-20 patients that we have now converted to buprenorphine.  
We will retrospectively review charts to collect genotype data, acute care utilization (ED, sickle 
infusion clinic and hospitalizations), COWS scores, sex, age and any complications that occurred 
with conversion.  These subjects will be asked to complete ASCQ-Me and Promis tools.  
b. 
(distinguish research procedures from those that are part of routine care).   
All research activities are noted with (R) above. 
c. Study duration and number of study visits required of research participants.   
Each participant will be enrolled for 3 years and will have up to 6 study visits with the possibility of 
completing the ASCQ-Me, BPI and Promis tools over the phone or online instead of coming in for a 
study visit.  The initial visit is part of routine care that we provide for conversion from opioids to 
buprenorphine. 
d. Blinding, including justification for blinding or not blinding the trial, if applicable. NA 
e. Justification of why participants will not receive routine care or will have current therapy 
stopped.  
NA 
f. Justification for inclusion of a placebo or non-treatment group. NA 
g. Definition of treatment failure or participant removal criteria. NA 
h. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely.  
NA this is an observational trial.  
 
5. Inclusion/Exclusion Criteria 
a. Inclusion Criteria: 
1. Has SCD, any genotype  
2. Is being converted from full agonist opioid therapy to buprenorphine.  
3. Able to provide consent  
4. Is between the ages 18 and 100. 
 
b. Exclusion Criteria:  
1. Unwilling to sign consent.   
2. Medical disorder, condition, or history that in the investigator’s judgement would impair 
the patient's ability to participate or complete this study or render the patient to be 
inappropriate for enrollment.  
 

 
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6. Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used.  
NA 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed. NA 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered. NA 
 
7. Study Statistics 
a. Primary outcome variable.  
Primary Endpoint: This will be a descriptive study assessing the safety and benefit of converting 
subjects from full agonist opioids to buprenorphine. Data will be collected on need for hospitalization 
within 72 hours of conversion due to withdrawal induced VOC, as well as average COWS scores.  
b. Secondary outcome variables.  
Secondary Endpoint: Measurement of quality of life and decreased pain measured by the BPI, ASCQ-
Me, PROMIS Pain Interference, PROMIS Physical Function and decreased acute care utilization.  
c. Statistical plan including sample size justification and interim data analysis.  
Descriptive study: Paired t-test will be used to compare patient’s results on surveys and acute care 
utilization pre- and post- conversion.  
d. Early stopping rules.   
NA 
8. Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency.   
b. Participants may feel uncomfortable filling out surveys. Steps taken to minimize the risks.   
Participants can stop filling out surveys at any time.  
c. Plan for reporting unanticipated problems or study deviations.  
All study deviations and adverse events will be reported to the IRB.  
d. Legal risks such as the risks that would be associated with breach of confidentiality. NA 
e. Financial risks to the participants.  
NA. 
 
9. Benefits 
Description of the probable benefits for the participant and for society.  
If successful we anticipate that participants will have an improved quality of life with less chronic pain and 
fewer visits for acute pain management.  For society Identifying alternative treatment options for pain 
management in people with sickle cell disease will help others who are suffering.  
 
10. Payment and Remuneration 
Detail compensation for participants including possible total compensation, proposed bonus, and 
any proposed reductions or penalties for not completing the protocol.   
Participants will be compensated $20.00 for each follow-up visit which is not part of usual care. Other costs 
associated with participation will be part of standard care.  
 
11. Costs 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify who will 
pay for them.   
NA 
 

 
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[5]  O. Platt, B. Thorington, D. Brambilla, P. Milner, W. Rosse, E. Vichinsky and T. Kinney, "Pain in sickle cell disease. 
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