Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety, and Pharmacokinetics of GMI-1070, A Pan-Selectin Inhibitor, In Subjects Hospitalized For Sickle Cell Vaso-Occlusive Crisis
Brief Summary: GMI-1070 is a new drug that may reduce the stickiness of cells in the blood. The purpose of this study is to evaluate whether GMI-1070 can reduce the time it takes for pain to go away in patients with vaso-occlusive crisis (also known as a sickle cell pain crisis). The study will also collect information on the safety of GMI-1070, how much of the drug is in the blood and urine, and if there are any other effects when used in patients who are in the hospital for a sickle cell pain crisis.


Options:
A: Inclusion Criteria:

1. Age between 18 and 55 years
2. Have confirmed diagnosis of sickle cell anemia or sickle beta zero thalassemia
3. Have a serum creatinine \</= 1.2 mg/dl
4. Have serum transaminase values \< 3 times upper limits of normal
5. Have a platelet count \>/= 150 x 10\^9/L
6. Have normal baseline coagulation profile
7. Sudden onset of pain involving one or more sites and typical of usual pain episodes
8. Have adequate intravenous access
9. Be able to understand the requirements of the study and be willing to give informed consent
10. Women of child-bearing age must be practicing (and will continue to practice for the course of the study) an adequate method of contraception (oral contraception, depo-provera, bilateral tubal ligation or barrier method)

Exclusion Criteria:

1. Have a baseline hemoglobin \< 6.0 gm/dl
2. Have a history of major gastrointestinal bleeding or a bleeding diathesis
3. Have an ongoing episode of acute chest syndrome
4. Have a past history of clinically overt stroke(s)
5. Have severe hypertension (systolic blood pressure \> 200mmHg and/or diastolic BP \>110mmHg) not adequately controlled on hypertensive medication
6. Have had major surgery within the six weeks preceding enrollment
7. Are pregnant or breastfeeding
8. Are on chronic anticoagulation or antiplatelet (including non-steroidal anti-inflammatory drugs) therapy
9. Have a history of metastatic cancer
10. Are on a chronic transfusion program or have received a blood transfusion in the prior 8 weeks
11. Have a positive urine toxicology screen for phencyclidine, cocaine or amphetamines.
12. Have a history of alcohol abuse
13. Have received any investigational drugs within the past 4 weeks.
B: Inclusion Criteria:

* Adult patients with SCD of any phenotype

Exclusion Criteria:

* Patient has a history of allergic reaction to either diamorphine/morphine or ibuprofen
* Patient has contraindications to diamorphine/morphine or ibuprofen, e.g. peptic ulcer disease, non-steroidal anti-inflammatory drug (NSAID)-induced asthma
* Patient in a drug dependency programme
* Patient is on renal dialysis
* Stroke within the last 6 weeks
* Platelet count less than 50 x 10\^9/l
* Patient is pregnant or breastfeeding
* Doctor unwilling to randomise the patient for other reasons
* Previous participation in the trial
* Patient receiving drug treatment with which opioids or NSAIDs are likely to interact significantly
* Stage 1 - 5 chronic kidney disease (ref Appendix 2), including urine protein: creatinine ratio of \>50 (Because the ibuprofen dose is substantial it is felt that precautions should be taken to exclude those who have any signs of chronic kidney disease. One of the signs of kidney disease is "persistent proteinuria". Therefore, the patient who intermittently has proteinuria(which could be due to other reasons) could still participate.)
* Oxygen saturation by pulse oximetry \<94%
* Participation in another clinical trial within the last month
C: Inclusion Criteria:

* Sickle Cell Disease: Hemoglobin diagnosis of SS (two copies of the hemoglobin S gene), SC (one copy of the hemoglobin S gene and one copy of the hemoglobin C gene), SD (one copy of the hemoglobin S gene and one copy of the hemoglobin D gene), or S-β thalassemia (β+ or β0)
* Male or female age ≥ 10 years.
* Typical vaso-occlusive pain that is not adequately controlled in an ambulatory or acute care setting and which is expected to require \> 24 hours of hospital care.
* Pain Intensity Visual Analog (10 cm scale) score ≥ 4.5 cm, measured immediately after obtaining informed consent.
* Adults willing and able to give informed consent; parents willing and able to give permission for study participation by their children; minor subjects (ages 10-17) willing and able to provide assent.
* Ability to read/write English.

Exclusion Criteria:

* Medical Indication

  * Presence of significant liver disease (ALT \> 3 times institutional upper limit of normal, or direct bilirubin \> 0.8 mg/dl within preceding 3 months)
  * Presence of significant renal dysfunction (within preceding 3 months, creatinine ≥ 1.2 mg/dl for ages \>18 yrs, or ages 10-18 yrs creatinine ≥ 1.0 mg/dl)
  * Oxygen saturation by pulse oximetry ≤ 92% on room air at study entry
  * Any other medical condition that renders the subject unable to or unlikely to complete the study or which would interfere with optimal participation in the study or which poses significant risk to the subject from study treatment including but not limited to:
  * Concurrent acute chest syndrome
  * Right upper quadrant pain
  * Symptomatic sleep apnea
  * Brain injury or doses of opioids that preclude potential subjects' capacity to give informed consent.
* Known (documented) hypersensitivity/intolerance to morphine and/or hydromorphone.
* Clinically significant opioid tolerance in the opinion of the investigator that precludes safe and/or effective dosing or requires, under current management, receiving the following long-acting oral opioids:

  * Methadone 40 mg/day
  * Sustained/Extended release oral morphine 120 mg /day
  * Oxycodone 80 mg/day
* Known pregnancy or currently breastfeeding.
* Poor venous access that in the investigator's judgment would preclude maintaining an IV throughout the admission.
* Currently participating in another research study.
* Previously randomized in the IMPROVE trial.
* Pain management in emergency department or Day Hospital ≥ 12 hours prior to decision to admit for inpatient care.
* Subject or physician preference for treatment with opioids other than morphine or hydromorphone.
D: Inclusion Criteria:

1. 12 to 60 years of age
2. Confirmed diagnosis of sickle cell disease (HbSS or HbS-β0thalassemia)
3. Diagnosis of VOC at the time of enrollment
4. Hospitalized or in process of admission at the time of enrollment
5. Able to receive the first dose of study drug within 24 hours of initial medical evaluation in the Emergency Department/clinic for VOC;

   o Subjects treated as an outpatient within the past 48 hours for the same VOC episode may be enrolled if dosing is also expected within 24 hours of their second (admitting) presentation.
6. Documented and observed written informed consent (and assent, where applicable)

Exclusion Criteria:

1. Infection, diagnosed or strongly suspected, as evidenced by one or more of the following:

   * Fever \>39°C (102.2°F)
   * In the presence of fever ≥38.5°C (101.3°F), 1 of the following:

     * Positive findings (suspicious for infection) on diagnostic tests, such as cerebral spinal fluid \[CSF\] evaluation, radiographs, or bacterial culture of normally sterile sites
     * Exam findings leading to diagnosed or strongly suspected bone or joint infection
     * Determination by physician that bacterial or serious systemic viral infection is likely (eg, influenza, mononucleosis)
     * Subjects may be included with uncomplicated urinary tract infections (provided they do not have fever ≥38.5° C \[101.3° F\] or costo-vertebral angle \[CVA\] tenderness), and/or suspected minor viral syndromes (upper respiratory infection symptoms but no symptoms suggestive of bacterial infection other than uncomplicated otitis media or uncomplicated streptococcal pharyngitis)
2. Acute chest syndrome, diagnosed or strongly suspected, as evidenced by a new infiltrate on chest radiograph, and 1 or more of the following:

   * Fever \>39° C (102.2° F)
   * Hypoxia (confirmed by arterial blood gases \[ABG\] with paO2 \<70 mmHg)
   * Chest pain
   * Suspicious findings on exam (tachypnea, intercostal retractions, wheezing, and/or rales)
3. Sickle cell disease (SCD) pain atypical of VOC, including hepatic or splenic sequestration, cholecystitis, or pneumonia.
4. Acute stroke, acute priapism, severe avascular necrosis of the hip/shoulder when the presenting pain is only in the affected hip/shoulder
5. Serum creatinine:

   * \>1.2 mg/dL for subjects 16 to 60 years of age
   * \>1.0 mg/dL for subjects 12 to 15 years of age
6. Alanine transaminase (ALT/SGPT) \>2x upper limit of normal (ULN) (based on clinic laboratory normal range)
7. Hemoglobin \<5 g/dL
8. Platelets \<100,000/mm3
9. Recent (within the past 30 days) major surgery, hospitalization for other than VOC, documented serious bacterial infection requiring antibiotic treatment, or significant bleeding
10. Hospitalization for uncomplicated VOC, or treated with parenteral pain medications in other medical settings such as the emergency department or day hospital for uncomplicated VOC, within past 14 days.

    o Subjects may be included if treated as an outpatient within the past 48 hours for the same VOC episode.
11. Recent (within the past 90 days) cerebrovascular accident, transient ischemic attack, or seizure
12. pRBC transfusions in the past 14 days
13. Systemic steroid therapy within 48 hours prior to enrollment or expectation that therapy may be used during the study (inhaled or topical steroids are allowed)
14. For those on chronic or long-acting opioids, a change in dose in the past 14 days OR pain requiring medical attention in the past 14 days (change in opioid medication for acute pain in the past 48 hours and directly related to this VOC admission is allowed)
15. Greater than 5 episodes of hospitalization for VOC in the past 6 months (180 days)
16. Medical or psychiatric condition that, in the opinion of the investigator, may pose a risk to the subject for participation or interfere with the conduct or results of the study
17. Currently receiving, or has received within the previous 4 weeks, any other investigational agent
18. Previous administration of GMI-1070
19. Expectation that the subject will not be able to be followed for the duration of the study
20. Pregnant or lactating female; or female of childbearing potential or male unable or unwilling to comply with birth control methods or abstinence during the course of the study
21. Active use of illicit drugs and/or alcohol dependence, as determined by the investigator

Answer: D