A Study to Evaluate the Efficacy, Safety and Tolerability of IMU-838 as Addition to Investigator's Choice of Standard of Care Therapy, in Patients With Coronavirus Disease 19 (COVID-19)

Study Overview
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Brief Summary
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At present there is no approved drug treatment for Covid-19. In this study we plan to investigate if an experimental drug called IMU-838 (vidofludimus calcium) can improve your symptoms, prevent worsening that would initiate further treatments such as ventilation, and can lower your virus number if given in addition to your doctor's choice of standard therapy. We will also test if IMU-838 has any side effects and measure the level of IMU 838 in your blood. Experimental drug means that it is not yet authorized for marketing in your country. To date approximately 600 individuals have received IMU-838 (or a drug similar to IMU-838 that contains the same active substance as IMU-838) in research studies.

Detailed Description
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The trial consists of a Phase 2 proof-of-concept phase (Part 1) with the option to extend enrollment (without interruption) to Phase 3 (Expansion Phase, Part 2). This trial is a multicenter, double-blind, placebo-controlled, randomized, parallel-group trial to evaluate the safety and efficacy of IMU-838 as addition to investigator's choice of SoC treatment in patients with COVID-19. Eligible patients will be centrally randomized 1:1 to twice-daily (BID) oral 22.5 mg IMU-838 (45 mg/day + SoC) or placebo (+ SoC). Randomization will be stratified by age (< or >=65 years) and antiviral therapy (no antivirals, Hydroxychloroquine and Chloroquine, all other antivirals). Adaptive sequential trial design and overall trial design The trial uses an adaptive sequential design. An IDMC will review unblinded data and provide the Sponsor with recommendations regarding modifications of sample size and trial conduct. A 1st interim analysis (IA1) will be performed after approximately 200 patients have completed the trial (either as scheduled or prematurely), while enrollment continues. If no activity of IMU 838 is observed by the IDMC in this IA, further patient enrollment will be stopped, and a final analysis of Part 1 will be performed (FA1). It is expected that the final analysis of Part 1 will include approximately 230 patients. If the IA1 results indicate activity of IMU-838 in COVID-19, the trial may be extended to Part 2 with a revised sample size derived by the IDMC based on IA1 results and with possible other trial adjustments. If the trial is extended into Part 2, a 2nd IA (IA2) is planned after approximately two-thirds of patients (based on the overall global sample size [Part 1 and Part 2 combined]) have been enrolled to potentially adjust sample size and other trial features if needed. The final analysis of the trial (FA2) will then be done after all patients have completed Part 2. In addition, an early interim safety analysis will be performed and evaluated by the IDMC after 30 patients have been enrolled to assess unblinded safety data. Further safety analyses can be initiated at any time by the IDMC or Sponsor when new safety signals are identified within this or other trials of IMU-838. Screening Patients can be screened for a maximum of 2 days (from Day -2 to Day 0) and eligible patients will be randomized on Day 0 and treated with IMP + SoC for 14 days. It is encouraged to screen potential participants immediately at the day of hospitalization (including informed consent, assessment of inclusion/exclusion criteria, screening laboratory tests all done locally, assessment of clinical and blood gas criteria) and randomize patients on the same day (Day 0). To assess eligibility criteria, existing local laboratory values obtained within 48 hours of randomization can also be used, except for testing of positive status of SARS-CoV-2 infection where a 4-day window is allowed. IMP administration should start as quickly as possible after randomization and first IMP intended to be given in the evening of the screening day (Day 0). Blinded Treatment period (Day 0 to Day 13) and Day 14 (end-of-treatment) The first dose of IMP (2 tablets) should always be given on Day 0 (allowed range for first dose: 12:00 noon on Day 0 to 02:00 a.m.). All further IMP doses are 1 tablet each in the morning and evening. Information about the status and patient care are continuously obtained and documented once or twice daily. After the last IMP dose in the evening of Day 13, the end-of-treatment assessments will be done on Day 14. Blood sampling for IMU-838 trough values must be performed in the morning around the time the morning dose was usually taken by the respective patient. Patients may then continue to receive SoC without any further restrictions on concomitant medications as during the 14-day BT period . Day 28 Visit (EoS) The patient should return for the final trial visit on Day 28 (EoS). If IMP is prematurely discontinued for any reason, the EoS visit should always be conducted on Day 28 and no earlier EoS should be performed. If patients withdraw from IMP prematurely, they should be encouraged to allow the EoS visit as part of the follow-up. If the patient dies during the trial, the investigator should indicate that this visit was not performed. However, even if no EoS visit was performed, information about patient status should be reported on the EoS page in the case report form. If the patient refuses any EoS visit or the patient is lost to follow-up, it is permissive in this trial that the investigator contacts the patient, the family of the patient or the referring physician by phone or email to obtain status of life information, or is able to search in registers or publicly available information for such status of life information.

Official Title
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A Prospective, Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Study to Evaluate the Efficacy, Safety and Tolerability of IMU-838 as Addition to Investigator's Choice of Standard of Care Therapy, in Patients With Coronavirus Disease 19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: IMU-838
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients at least 18 years old (may be extended to include also children 12 years or older after the 1st interim analysis) Admitted to the hospital or other medical in-patient treatment facility for treatment of COVID-19 The hospitalization needs to be for medical reasons (treatment of COVID-19 disease) and cannot be for social reasons or due to housing insecurity. For US sites only: If the investigator would commonly hospitalize the patient but for healthcare resource reasons decides to treat the patient in a specially designed out-patient setting, then such patients are also allowed to enter the trial (please note that in this case the patient would be counted as clinical status category 3). The investigator then must assure that the patient has at least a twice daily assessment by qualified trial personnel and all laboratory assessments can be adequately performed as per protocol. The Sponsor reserves the right to discontinue this option via administrative letter if such assurances cannot be met by any site. SARS-CoV-2 infection confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) test in a nasopharyngeal, oropharyngeal or respiratory sample at ≤4 days before randomization Moderate COVID-19 disease defined as fulfilling clinical status category 3 or 4 on the WHO 9-point ordinal scale [21]: Category 3: Hospitalized (see note above for US only), virus-positive, no oxygen therapy with the following conditions: The hospitalization needs to be for medical reasons (treatment of COVID-19 disease) and cannot be for social reasons or due to housing insecurity Category 4: Hospitalized, virus-positive, oxygen by mask or nasal prongs (excluding high-flow oxygen therapy) with the following conditions: Peripheral capillary oxyhemoglobin saturation (SpO2) >92% at maximum of 6 liters oxygen flow per minute Stable respiratory rate ≤30 breaths/min at maximum of 6 liters oxygen flow per minute Presence of at least 1 symptom characteristic for COVID-19 disease i.e., fever, cough or respiratory distress Willingness and ability to comply with the protocol Written informed consent given prior to any trial-related procedure For women of childbearing potential: Application of a highly effective method of birth control (failure rate less than 1% per year when used consistently and correctly) together with a barrier method between trial consent and 30 days after the last intake of the IMP. Highly effective forms of birth control are those with a failure rate less than 1% per year and include: oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal contraceptives associated with inhibition of ovulation oral, injectable, or implantable progestogen-only hormonal contraceptives associated with inhibition of ovulation intrauterine device or intrauterine hormone-releasing system bilateral tubal occlusion vasectomized partner (i.e., the patient's male partner underwent effective surgical sterilization before the female patient entered the clinical trial and is the sole sexual partner of the female patient during the clinical trial) sexual abstinence (acceptable only if it is the patient's usual form of birth control/lifestyle choice; periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are no acceptable methods of contraception) Barrier methods of contraception include: Condom Occlusive cap (diaphragm or cervical/vault caps) with spermicidal gel/film/cream/suppository Male patients must agree not to father a child or to donate sperm starting at Screening, throughout the clinical trial and for 30 days after the last intake of the IMP. Male patients must also abstain from sexual intercourse with a female partner (acceptable only if it is the patient's usual form of birth control/lifestyle choice), or use adequate barrier contraception during treatment with the IMP and until at least 30 days after the last intake of the IMP, and if they have a female partner of childbearing potential, the partner should use a highly effective contraceptive method as outlined in inclusion criterion 8 if they have a pregnant partner, they must use condoms while taking the IMP to avoid exposure of the fetus to the IMP Exclusion Criteria: Underlying disease-related exclusion criteria Involvement in the trial is not in the patient's best interest according to the investigator's decision, including the presence of any condition that would, in the assessment of the investigator, not allow the protocol to be followed safely Note: The investigator should particularly consider exclusion of patients at increased risk for serious or fatal AEs in case of worsening of the pulmonary perfusion. This includes, but is not limited to, pre-existing pulmonary hypertension, severe chronic respiratory disease, severely increased risk for thromboembolic complications and moderate to severe left ventricular ejection fraction (LVEF) dysfunction. In addition, other known risk factors of highest risk of mortality in COVID-19 patients should be considered. Presence of respiratory failure, shock, and/or combined failure of other organs that requires ICU monitoring in the near foreseeable future Critical patients whose expected survival time <48-72 hours Presence of the following laboratory values at screening: White blood cell count (WBC) <1.0 x 109/L Platelet count <100,000/mm³ (<100 x 109/L) Total bilirubin>2 x ULN Alanine aminotransferase (ALT) or gamma glutamyl transferase (GGT) >5 x ULN Participation in any other interventional clinical trial Hospitalization primarily for other reasons than COVID-19 (including primarily for concomitant conditions during ongoing SARS-CoV-2 infection) Anticipated transport to a different hospital or institution, in particular when such transport is anticipated for pending ECMO or RRT treatment Clinical suspicion of a bacterial superinfection at Screening IMP-related exclusion criteria Patients who cannot take drugs orally Allergic or hypersensitive to the IMP or any of the ingredients Use of the following concomitant medications is prohibited from Screening to end of treatment with IMP in this trial (up to Day 14) if not indicated otherwise in this protocol: Concurrent use of any mycophenolate mofetil or of methotrexate exceeding 17.5 mg weekly Any medication known to significantly increase urinary elimination of uric acid, in particular lesinurad (Zurampic™) as well as uricosuric drugs such as probenecid Current treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, bosutinib, sorafenib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib Any drug significantly restricting water diuresis, in particular vasopressin and vasopressin analogs Use of rosuvastatin at daily doses higher than 10 mg Arbidol and Colchicine Any use of other DHODH inhibitors, including teriflunomide (Aubagio™) or leflunomide (Arava™) Chloroquine and Hydroxychloroquine during the entire trial unless taken for indicated use before entering the trial Use of any investigational product within 8 weeks or 5x the respective half-life before the date of informed consent, whichever is longer, and throughout the duration of the trial General exclusion criteria Patients who have a do not intubate or do not resuscitate order (unless the patient waives in writing this order and will allow intubation for the duration of the trial period) Patients with end-stage liver disease (Child Pugh C score) History or presence of serious or acute heart disease such as uncontrolled cardiac dysrhythmia or arrhythmia, uncontrolled angina pectoris, cardiomyopathy, or uncontrolled congestive heart failure (New York Heart Association [NYHA] class 3 or 4) Note: NYHA class 3: Cardiac disease resulting in marked limitation of physical activity. Patients are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain. NYHA class 4: Cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. Legal incapacity, limited legal capacity, or any other condition that makes the patient unable to provide consent for the trial Pregnant or breastfeeding An employee of an investigator or Sponsor or an immediate relative of an investigator or Sponsor Patients institutionalized due to judicial order

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: double-blind, placebo-controlled, randomized, parallel-group trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMU-838<br>twice-daily (BID) oral 22.5 mg IMU-838 (45 mg/day + SoC) | Drug: IMU-838<br>* Tablets will be taken BID with a glass of water (if possible); one tablet each in the morning (15 to 50 min before a meal if applicable), and in the evening (2 hours after any meal if applicable). If the patient is intubated for ventilation, IMP is to be given via a gastric tube. The tablet has no coating and a homogeneous content and can be crushed into smaller pieces (if necessary) for dosing via gastric tube.<br>* Other names: vidofludimus calcium;|
| Placebo Comparator: Placebo<br>twice-daily (BID) oral placebo (+ SoC) | Other: Placebo<br>* Matching placebo, twice-daily administration BID as described for the test product, identical number of tablets as given for IMU-838<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients without any need* for INV until end-of-study (EoS) | Clinical | Throughout the Study (Day 0 to Day 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of ICU treatment until EoS | Key Secondary | Throughout the Study (Day 0 to Day 28 ) | 
| 28-day all-cause mortality | Key Secondary | Throughout the Study (Day 0 to Day 28 ) | 
| Time to clinical improvement | Efficacy: defined as the time from first dose of investigational medicinal product (IMP) to an improvement of at least 2 points on the WHO 9 category ordinal scale , or live discharge from hospital without oxygen supplementation, whichever comes first | Throughout the Study (Day 0 to Day 28 ) | 
| Duration of hospitalization | Efficacy: Duration of hospitalization (for US sites only: or treatment in special outpatient setting in lieu of hospitalization due to resource restraints) | Throughout the Study (Day 0 to Day 28 ) | 
| Proportion of patients both for all patients and surviving patients free of renal-replacement therapy (RRT)* until EoS | Efficacy | Throughout the Study (Day 0 to Day 28 ) | 
| Proportion of patients both for all patients and surviving patients free from extracorporeal membrane oxygenation (ECMO)* until EoS | Efficacy | Throughout the Study (Day 0 to Day 28 ) | 
| Proportion of patients free of INV until Days 6 and 14* | Efficacy | Throughout the Study (Day 0 to Day 28 ) | 
| Proportion of patients free of RRT until Days 6 and 14* | Efficacy | Day 0 to Days 6 and 14 | 
| Proportion of patients free ECMO until Days 6 and 14* | Efficacy | Day 0 to Days 6 and 14 | 
| Proportion of patients with improvement of at least 2 points (from randomization) on the 9-category WHO ordinal scale1 on Days 6, 14, and 28 | Efficacy | on Days 6, 14, and 28 | 
| Proportion of patients with auxiliary oxygen therapy (including all types of oxygen therapy) on Days 6, 14, and 28 | Efficacy | on Days 6, 14, and 28 | 
| Proportion of patients with clinical recovery: Axillary temperature ≤36.6 ℃, or oral temperature ≤37.2 ℃, or rectal or tympanic temperature ≤37.8 ℃; | Efficacy | Throughout the Study (Day 0 to Day 28 ) | 
| Proportion of patients with clinical recovery: Respiratory frequency ≤24 times/min without oxygen inhalation; and | Efficacy | Throughout the Study (Day 0 to Day 28 ) | 
| Proportion of patients with clinical recovery: Oxygen saturation ≥98% without oxygen inhalation | Efficacy | Throughout the Study (Day 0 to Day 28 ) | 
| Proportion of patients with clinical improvement, defined as the time from first dose of IMP to an improvement of at least 2 points on the WHO 9 category ordinal scale, or live discharge from hospital without oxygen supplementation, whichever comes first | Efficacy | Throughout the Study (Day 0 to Day 28 ) | 
| Clinical patient status on the 9-category WHO ordinal scale1 on Days 6, 14, and 28 | Efficacy | on Days 6, 14, and 28 | 
| Duration of INV | Efficacy | Throughout the Study (Day 0 to Day 28 ) | 
| Duration of ECMO | Efficacy | Throughout the Study (Day 0 to Day 28) | 
| Duration of RRT | Efficacy | Throughout the Study (Day 0 to Day 28) | 
| Duration of auxiliary oxygen therapy (including all types of oxygen therapy) | Efficacy | Throughout the Study (Day 0 to Day 28) | 
| Duration of hospitalization for survivors | Efficacy | Throughout the Study (Day 0 to Day 28) | 
| The rate of ICU* admission on Days 6, 14, and 28 | Efficacy | on Days 6, 14, and 28 | 
| Hospital-free days | Efficacy | Throughout the Study (Day 0 to Day 28) | 
| Time from IMP treatment initiation to death | Efficacy | Throughout the Study (Day 0 to Day 28) | 
| Time to first prescription of INV | Efficacy | Throughout the Study (Day 0 to Day 28) | 
| Time to first prescription of RRT | Efficacy | Throughout the Study (Day 0 to Day 28) | 
| Time to first prescription of ECMO | Efficacy | Throughout the Study (Day 0 to Day 28) | 
| Time to first prescription of INV, RRT, and ECMO | Efficacy | Throughout the Study (Day 0 to Day 28) | 
| Time to ICU admission | Efficacy | Throughout the Study (Day 0 to Day 28) | 
| Cumulative dose of vasoactive therapies and days with vasoactive therapies (daily until Day 14) | Efficacy | Day 0 to day 14 | 
| Time to clinical recovery | Efficacy | Throughout the Study (Day 0 to Day 28) | 
| Morning trough plasma levels of IMU-838 on Days 0, 1, 2, 3, 6, 14, and 28 | Pharmacokinetics | on Days 0, 1, 2, 3, 6, 14, and 28 | 
| Correlation of trough levels (quartiles) to selected clinical outcomes (Clinical improvement accoding to WHO criteria) | Pharmacokinetics | on Days 0, 1, 2, 3, 6, 14, and 28 | 
| Adverse events (AEs) and serious AEs | Safety | Throughout the Study (Day 0 to Day 28) | 
| Vital signs: height | Safety Height in centimeters will be recorded without shoes. Changes in vital signs judged by the investigator as clinically significant will be reported as an AE. | only at Screening | 
| Vital signs: weight | Safety Weight in kilograms will be recorded without shoes. Changes in vital signs judged by the investigator as clinically significant will be reported as an AE. | Throughout the Study (Day 0 to Day 28) | 
| Vital signs: body temperature (ºC) | Safety Body temperature can be measured axillary, oral, rectal or tympanic, but should be always measured by the same method for a patient. Changes in vital signs judged by the investigator as clinically significant will be reported as an AE. | Throughout the Study (Day 0 to Day 28) | 
| Vital signs: pulse rates, | Safety Pulse must be measured with the patient in a seated position (if possible), after at least 5 minutes at rest. Changes in vital signs judged by the investigator as clinically significant will be reported as an AE. | Throughout the Study (Day 0 to Day 28) | 
| Vital signs: systolic and diastolic blood pressures | Safety Blood pressure (systolic and diastolic) must be measured with the patient in a seated position (if possible), after at least 5 minutes at rest. Changes in vital signs judged by the investigator as clinically significant will be reported as an AE. | Throughout the Study (Day 0 to Day 28) | 
| Clinical laboratory parameters: blood chemistry | Safety | Throughout the Study (Day 0 to Day 28) | 
| Clinical laboratory parameters: hematology | Safety | Throughout the Study (Day 0 to Day 28) | 
| Clinical laboratory parameters: urinalysis | Safety | Throughout the Study (Day 0 to Day 28) | 
| 12-lead electrocardiogram: heart rate | Safety | Day 0 to Day 6 and Day 28 | 
| 12-lead electrocardiogram: PQ-interval | Safety | Day 0 to Day 6 and Day 28 | 
| 12-lead electrocardiogram: QRS-interval | Safety | Day 0 to Day 6 and Day 28 | 
| 12-lead electrocardiogram: QT interval | Safety | Day 0 to Day 6 and Day 28 | 
| 12-lead electrocardiogram: the heart rate-corrected QTc interval (according to Bazett's formula) | Safety | Day 0 to Day 6 and Day 28 | 
| Temperature | Safety | Throughout the Study (Day 0 to Day 28) | 
| D-dimer | Disease markers | Throughout the Study (Day 0 to Day 28) | 
| Lactate dehydrogenase (LDH) | Disease markers | Throughout the Study (Day 0 to Day 28) | 
| C-reactive protein | Disease markers | Throughout the Study (Day 0 to Day 28) | 
| Troponin I | Disease markers | Throughout the Study (Day 0 to Day 28) | 
| Procalcitonin | Disease markers | Throughout the Study (Day 0 to Day 28) | 
| Correlation of disease markers to selected clinical outcomes (Clinical improvement accoding to WHO criteria) | Disease markers | Throughout the Study (Day 0 to Day 28) | 
| Severe Acute Respiratory Syndrome Coronavirus Virus (SARS-CoV-2) mean viral load - log10 copies in spontaneous sputum and nasopharyngeal swab samples: Decrease of SARS-CoV-2 viral load | Virologic markers | Throughout the Study (Day 0 to Day 28) | 
| Severe Acute Respiratory Syndrome Coronavirus Virus (SARS-CoV-2) mean viral load - log10 copies in spontaneous sputum and nasopharyngeal swab samples: Time course of SARS-CoV-2 viral load | Virologic markers | Throughout the Study (Day 0 to Day 28) | 
| Qualitative virologic clearance in spontaneous sputum and nasopharyngeal swab samples (= 2 consecutive negative SARS-CoV-2 reverse transcriptase polymerase chain reaction tests at least 24 hours apart) | Virologic markers | Throughout the Study (Day 0 to Day 28) | 
| Rate of conversion to a negative SARS-CoV-2 (qualitative) test on Days 6, 14 and 28 | Virologic markers | on Days 6, 14 and 28 | 
| Time to conversion to a negative SARS-CoV-2 (qualitative) test | Virologic markers | Throughout the Study (Day 0 to Day 28) | 
| Interleukin (IL)-17 | Biomarkers | Day 0, 6, 14 and Day 28 | 
| Interleukin (IL)-1ß | Biomarkers | Day 0, 6, 14 and Day 28 | 
| Interleukin (IL)-6 | Biomarkers | Day 0, 6, 14 and 28 | 
| interferon gamma (IFNγ) | Biomarkers | Day 0, 6, 14 and 28 | 
| tumor necrosis factor alpha | Biomarkers | Day 0, 6, 14 and 28 | 
| Immunoglobulin (Ig)A and IgG antibodies against SARS-CoV-2: • Time to appearance of IgA and/or IgG antibodies | Serologic markers | Day 0, 6, 14 and 28 | 
| Immunoglobulin (Ig)A and IgG antibodies against SARS-CoV-2: • Proportion of patients with IgA and/or IgG antibodies on Days 6, 14, and 28 | Serologic markers | Day 0, 6, 14 and 28 |