Patient-Reported Outcomes: Descriptors of Nociceptive and Neuropathic Pain and Barriers to Effective Pain Management in Adult Outpatients With Sickle Cell Disease

Abstract To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points.

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Patient-Reported Outcomes and Economic Burden of Adults with Sickle Cell Disease in the United States: A Systematic Review

International Journal of General Medicine ◽

10.2147/ijgm.s257340 ◽

2020 ◽

Vol Volume 13 ◽

pp. 361-377

Author(s):

Soyon Lee ◽

Diana K Vania ◽

Menaka Bhor ◽

Dennis Revicki ◽

Seye Abogunrin ◽

...

Keyword(s):

United States ◽

Systematic Review ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Economic Burden ◽

Patient Reported Outcomes ◽

The United States ◽

Cell Disease ◽

Patient Reported

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POST Marketing Observational Study of Children (6 years or older) Treated with Deferasirox (Exjade ICL 670)-One Year analysis

Blood ◽

10.1182/blood.v118.21.5295.5295 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5295-5295

Author(s):

Nagina Parmar ◽

Manroop Singh ◽

Isaac Odame ◽

Melanie Kirby

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Patient Reported Outcomes ◽

Chelation Therapy ◽

Descriptive Statistics ◽

Cell Disease ◽

Outcomes Measures ◽

Short Period ◽

Patient Reported

Abstract Abstract 5295 In 2006, deferasirox was licensed in Canada for use in children over the age of 6 years. Deferasirox (Exjade â, ICL 670) is an orally active iron chelators which represents the new class of tridentate iron chelator. Deferasirox has been formulated as a dispersible tablet based on technical feasibility, stability, and adequate bioavailability. Deferasirox has been shown to be as effective as deferral (DFO) and has a clinically manageable safety profile (the most common side effects are gastrointestinal disturbances and rashes). Few studies have been conducted to compare the satisfaction, convenience, activity limitations, and patient preferences of deferasirox in comparison with DFO in sickle cell and thalassemia patients. The purpose of the present study was to evaluate the long-term response of deferosirox in iron-overloaded children aged 6 years or older treated with transfusion dependent anemia and secondary objective was to collect and analyze the following parameters such as serum ferrtin, SLT, AST, creatinine, audiology and ophthalmology, liver iron concentrations (LIC) and patient reported outcomes measures over a period of 2 years from the start of deferasirox. The study population comprised of male and female patients aged 6 years or <17.99 with chronic iron overload related to blood transfusions in patients with Thalassemia and Sickle cell disease. Fifty-one patients were enrolled into this study at the Hematology Clinic, Hospital for Sick Children, Toronto, ON Canada. This study was observational and does not impose a therapy protocol, diagnostic/therapeutic interventions or a strict visit schedule. Patients were treated with deferasirox according to the local physician's judgment and in accordance with the local (country-specific) deferasirox prescribing information. Data were collected at study entry (baseline), and at 12 months. Patients were approached for the study after the ethics approval was obtained. All variables were explored and summarized using descriptive statistics such as means, standard deviation, median and ranges, counts and proportions, graphs as appropriate. Patients reported outcomes measures questionnaires were given after the written consent/assent was obtained. Statistical analysis was done by descriptive statistics and paired t-test. Of the 51 subjects, 30 were females, 21 were males, and median age for the patients was 14 ± 5.3. Out of 51 patients, 49 patients had thalassemia and two had sickle cell disease. All of the subjects were on desferal chelation therapy before the start of the deferasirox, Analysis of patient reported outcomes measures showed that majority of the patients (73%) were very satisfied with deferasirox, when they started and after 12 months on the study, however 1 patient who reported dissatisfaction in 2009, reported satisfaction in year 2010. The main reason for the deferasirox, treatment preference were relief of pain associated with injections (30%) and more convenient (35%) in administration. Other reasons given were improved sleep patterns (2%) and less disruption to the family (6%). At baseline and 12 months laboratory evaluations were as follows: Mean Creatinine values (88% of the patients) (baseline- 34.41±11.49, 12 months – 52.41 ± 19.82), Mean ALT (65% of the patients) (baseline- 41.73 ± 7.32, 12 months – 30.94 ± 5.30) and serum ferritin (baseline- 1995± 276, 12 month, 1833 ± 203). Mean LIC (baseline-11.08 ± 1.29, 12 months- 7.87 ± 1.12) evaluations showed the incremental decrease over time with 14/51 showed the values of <3 over a 12 months period. Chelation therapy was held for some patients for a short period to prevent toxicity related to the chelator. Mild (4/51) and moderate (1/51) hearing loss were observed in subjects over period from 2009–2010. Data will be collected after 24 months to evaluate their long-term responses and for comparative analysis. Further, we can conclude that given the high levels of satisfaction, it is likely that the quality of life and adherence to chelation treatment have improved for patients who are receiving the deferasirox treatment compared with previous subcutaneous chelation treatment. Disclosures: No relevant conflicts of interest to declare.

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Clinical trial considerations in sickle cell disease: patient-reported outcomes, data elements, and the stakeholder engagement framework

Hematology ◽

10.1182/hematology.2021000252 ◽

2021 ◽

Vol 2021 (1) ◽

pp. 196-205

Author(s):

Sherif M. Badawy

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Stakeholder Engagement ◽

Patient Reported Outcomes ◽

Outcomes Assessment ◽

Cell Disease ◽

Patient Centered ◽

Patient Reported

Abstract Patients with sickle cell disease (SCD) have significant impairment in their quality of life across the life span as a consequence of serious disease burden with several SCD-related complications. A number of disease-modifying therapies are currently available, yet long-term clinical benefits in real-world settings remain unclear. Over the past few years, a number of important initiatives have been launched to optimize clinical trials in SCD in different ways, including: (1) established panels through a partnership between the American Society of Hematology (ASH) and the US Food and Drug Administration; (2) the ASH Research Collaborative SCD Clinical Trials Network; (3) the PhenX Toolkit (consensus measures for Phenotypes and eXposures) in SCD; and (4) the Cure Sickle Cell Initiative, led by the National Heart, Lung, and Blood Institute. Electronic patient-reported outcomes assessment is highly recommended, and patient-reported outcomes (PROs) should be evaluated in all SCD trials and reported using Standard Protocol Items Recommendations for Interventional Trials guidelines. Patient-centered outcomes research (PCOR) approaches and meaningful stakeholder engagement throughout the process have the potential to optimize the execution and success of clinical trials in SCD with considerable financial value. This article reviews several clinical trial considerations in SCD related to study design and outcomes assessment as informed by recent initiatives as well as patient-centered research approaches and stakeholder engagement. A proposed hematology stakeholder-engagement framework for clinical trials is also discussed.

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Implementation of an Intravenous Lidocaine Guideline for Children and Adolescents with Sickle Cell Vaso-Occlusive Pain

Blood ◽

10.1182/blood-2021-151128 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2962-2962

Author(s):

Ugochukwu Agbakwuru ◽

Jacob D AuBuchon ◽

Bobi Toebe ◽

Anne LaBarge ◽

Jorge Di Paola ◽

...

Keyword(s):

Pain Management ◽

Side Effects ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Research Funding ◽

Management Service ◽

Intravenous Lidocaine ◽

Cell Disease ◽

Care Guideline ◽

Patient Reported

Abstract Introduction Sickle cell disease (SCD) affects approximately 100,000 Americans.[1] Vaso-occlusive episodes (VOEs) are the leading cause of hospitalization in SCD; in 2016, out of 134,000 SCD hospitalizations, 81% included VOE. [2] Opioids are the mainstay of VOE treatment, but side effects include sedation, hyperalgesia, and dependency risk. Lidocaine, which inhibits voltage-gated sodium channels in peripheral sensory nerves, is given intravenously (IV) for postoperative pain management and holds promise for VOE treatment.[3] At St. Louis Children's Hospital (SLCH), children admitted with VOEs receive an opioid by continuous infusion plus patient-controlled analgesia (PCA) and non-opioid adjuvants. In 2019, the Sickle Cell Disease Program and Pain Management Service jointly developed a guideline for VOE management that includes: 1. Standardized dosing of IV opioids and IV or oral NSAIDs 2. Pain management service consultation for all children age ≥10 y admitted with VOE 3. Initiation of IV lidocaine infusion (1-1.5 mg/kg/h x 48 h) within 24 h of admission for severe pain 4. Addition of non opioid adjuvants, such as muscle relaxants, topical agents, and agents for neuropathic pain 5. IV lidocaine is prescribed by the Pain Management Service. Patients are monitored for lidocaine side effects including tinnitus, perioral tingling, vital sign changes, and seizures. A 24 h serum lidocaine level is drawn to ensure levels are not supra-therapeutic. We aimed to evaluate the implementation of this care guideline, focused on IV lidocaine as a safe, tolerable and effective adjunct to opioids for VOE treatment in children. Methods This retrospective cohort study reviewed records of children with SCD age ≥10 years admitted for VOE at SLCH during 2018-2020. Data collected included patient demographics, impact on pain, lidocaine levels, and reported side effects. This study was approved by the institutional review board. Results We identified 61 patients (31 males), median age 15.7 y (range 9-21), with 174 IV lidocaine administrations during 164 hospitalizations. Hemoglobin (Hb) SS comprised 60.7% of the cohort; 32.8% had Hb SC disease, 4.9% had Hb Sβ0 thalassemia and 1.6% had Hb Sβ+ thalassemia. IV lidocaine was started within 24 h for 78.7% (129/164) of included admissions. The mean blood lidocaine level was 2.14 mcg/ml (SD 1.23). Of the 164 admissions, 9 individuals had lidocaine levels above the limit of 4.5 mcg/ml, none had symptoms of toxicity. Few side effects were noted: lip paresthesia in 1 child (lidocaine stopped, but received in future admissions); nausea in 1 child (declined lidocaine in future admissions); pain increase in 1 teen (lidocaine was stopped). One child stopped lidocaine infusions prematurely during 2 admissions due to refusal of phlebotomy for the lidocaine level. Overall, 59 children perceived benefit of IV lidocaine and chose to receive it again during later admissions. During 10 prolonged hospitalizations, a second 48-hour lidocaine infusion was given due to patient reported benefit. We identified falsely elevated lidocaine levels when subcutaneous lidocaine was used before phlebotomy, but no patients with high lidocaine levels experienced toxicity. We altered our response to supratherapeutic levels by pausing the lidocaine infusion, redrawing lab at a peripheral site without subcutaneous lidocaine contamination, and resuming lidocaine infusion if level was normal. Every repeated lidocaine level was within normal limits. Discussion In our cohort, IV lidocaine was safe, tolerable, and improved pain control. The care guideline was initiated within 24 hours for 78.7% of admissions. Mild side effects occurred in only 3 patients, highlighting safety. Future considerations include a prospective study focused on length of stay, patient-reported outcomes, opioid exposure, and factors influencing the care guideline's utilization. References: 1. American Society of Hematology. Sickle Cell Disease. www.hematology.org/Patients/Anemia/Sickle-Cell.aspx 2.Fingar K, Owens P, et al (2019). Characteristics of Inpatient Hospital Stays Involving Sickle Cell Disease, 2000-2016. Agency for Healthcare Research and Quality. https://hcup-us.ahrq.gov/reports/statbriefs/sb251-Sickle-Cell-Disease-Stays-2016.jsp 3.Dunn L, Durieux ME, (2017). Perioperative use of intravenous lidocaine. Anesthesiology, 126(4), 729-737. https://doi.org/10.1097/aln.0000000000001527 Disclosures Di Paola: CSL Behring: Consultancy, Honoraria. Hulbert: Pfizer: Current Employment, Current holder of individual stocks in a privately-held company; bluebird bio: Consultancy; Global Blood Therapeutics: Research Funding; Forma Therapeutics: Consultancy, Research Funding.

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Patient‐reported outcomes in sickle cell disease and association with clinical and psychosocial factors: Report from the sickle cell disease implementation consortium

American Journal of Hematology ◽

10.1002/ajh.25880 ◽

2020 ◽

Vol 95 (9) ◽

pp. 1066-1074 ◽

Cited By ~ 1

Author(s):

Mitchell R. Knisely ◽

Norma Pugh ◽

Barbara Kroner ◽

Rita Masese ◽

Victor Gordeuk ◽

...

Keyword(s):

Sickle Cell Disease ◽

Psychosocial Factors ◽

Sickle Cell ◽

Patient Reported Outcomes ◽

Cell Disease ◽

Patient Reported

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Evaluation of Longitudinal Pain Study in Sickle Cell Disease (ELIPSIS) by Electronic Patient-Reported Outcomes, Actigraphy, and Biomarkers

Blood ◽

10.1182/blood.2020006020 ◽

2020 ◽

Author(s):

Debra Pittman ◽

Patrick C Hines ◽

David Roger Beidler ◽

Denis Rybin ◽

Andrew L Frelinger ◽

...

Keyword(s):

Health Care ◽

Clinical Trials ◽

Sickle Cell Disease ◽

Health Care Utilization ◽

Sickle Cell ◽

Patient Reported Outcomes ◽

Care Utilization ◽

Cell Disease ◽

Patient Reported ◽

At Home

Clinical trials in sickle cell disease (SCD) often focus on health care utilization for painful vaso-occlusive crises (VOC). However, no objective, quantifiable pain biomarkers exist, pain is not specific to VOCs, health care utilization varies between patients, unreported at-home VOCs likely contribute to long-term outcomes, and patient-reported outcomes are seldom considered. This non-interventional, longitudinal, 6-month study aimed to develop tools to identify VOCs in SCD patients with or without health care utilization. Participants wore an actigraph device, tracking sleep and activity. SCD patients used an electronic patient-reported outcome (ePRO) tool collecting pain, medication, fatigue, and daily function. Patients self-reported when they experienced VOC pain (VOC day). Biomarkers were collected every 3 weeks (non-VOC). Self-reported VOCs triggered at-home or in-hospital blood collection. The study enrolled 37 participants with SCD; 35 completed the study. Participants reported 114 VOC events and 346 VOC days, of which 62.3% and 78.3%, respectively, were self-treated at home. The ePRO and actigraphy captured endpoints of pain, functionality, fatigue, activity, and sleep; each was significantly altered on VOC days compared with non-VOC days. Biomarkers collected at home or in hospital on VOC days were significantly altered compared with non-VOC baseline values, including leukocyte-platelet aggregates, microfluidic-based blood cell adhesion, interleukin-6, C-reactive protein, interleukin-10, tumor necrosis factor-alpha, and thrombin-antithrombin. ELIPSIS: demonstrates the feasibility of accurately monitoring out-of-hospital pain, using patient-reported VOC days as potential endpoints for clinical trials in SCD; showed changes in biomarkers and activity measured by actigraphy that may enable improved identification and assessment of VOCs.

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Challenges to management of pain in sickle cell disease

Thalassemia Reports ◽

10.4081/thal.2018.7482 ◽

2018 ◽

Vol 8 (1) ◽

Author(s):

Julie Kanter

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Patient Reported Outcomes ◽

Medical Providers ◽

Cell Disease ◽

Blood Disorders ◽

Pain Experience ◽

Multiple Dimensions ◽

Patient Reported ◽

Pharmacologic Agents

Sickle Cell Disease (SCD) is one of the most common blood disorders in the world. Pain is the primary reason for which individuals with SCD interact with the healthcare system. Generally speaking, there are two types of SCD pain: vaso-occlusive pain (or sickle cell disease crisis) and chronic pain caused by an accumulation of organ and tissue damage over time. However, despite its frequency, we have limited understanding about what causes pain in sickle cell disease, how best to manage pain in SCD and (most importantly) how to prevent pain in SCD. For medical providers, pain is also an elusive target due to the difficulty in objectively measuring pain and the importance of relying on patient reported outcomes. To face the challenges in managing pain in SCD, we will review the current understanding of the pathophysiology of vaso-occlusion, the multiple dimensions of the pain experience, and the current methods of measuring and managing pain. We will also review new pharmacologic agents undergoing clinical trials in SCD that will help to prevent pain and improve outcomes in SCD.

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